After his first Cruiserweight title reign ended, Mysterio began a feud with Ultimate Dragon over Dragon's J-Crown Championship, unsuccessfully challenging him at World War 3. In early 1997, he feuded with Prince Iaukea over the WCW World Television Championship. He challenged Iaukea for the title at SuperBrawl VII, which Mysterio lost after Lord Steven Regal attacked him. Mysterio lost again in a rematch for the title at Uncensored. He had short feuds for the rest of the year before he began a feud with his real-life friend and Cruiserweight Champion Eddie Guerrero. He defeated Guerrero in a Title vs. Mask match at Halloween Havoc for his second Cruiserweight Championship. On the November 10 edition of Nitro, he dropped the title back to Guerrero. They had a rematch at World War 3, which Mysterio lost.
On the January 15, 1998 edition of WCW Thunder, Mysterio defeated Juventud for his third Cruiserweight Championship, which he lost only nine days later to Chris Jericho at Souled Out. After the match, Jericho continued the beating by using a toolbox he found at ringside. This attack put Mysterio on the sidelines for six months before making his return at Bash at the Beach, where he defeated Jericho for the championship. The next night, however, the result was overturned and the belt returned to Jericho due to the interference by Dean Malenko.
Later that year, Eddie Guerrero formed a Mexican stable known as the Latino World Order (LWO) (a spin off of New World Order) that included nearly every luchador in the promotion. Mysterio continually refused to join and feuded with Guerrero and the LWO members, including winning a match against long time rival and LWO member Psychosis in a match at Road Wild. He, however, was finally forced to join the group via a stipulation after losing a match to Eddie Guerrero. Mysterio and his on-and-off tag team partner Billy Kidman joined him during the feud with LWO despite Mysterio being a part of the group. His alliance with Kidman was formed after Mysterio helped Kidman defeat Juventud for the Cruiserweight Title at World War 3. Mysterio feuded with Kidman over his Cruiserweight Championship being defeated at Starrcade in a Triangle match also involving Juventud and again at Souled Out in a Fatal Four-Way match also involving Psychosis and Juventud. As the two factions of nWo reformed - nWo Hollywood and nWo Wolfpac - they demanded the LWO's disbanding. Mysterio refused to take off his LWO colors and was physically beaten as a result.
In the summer of 1999, Mysterio teamed with long time friend Konnan, becoming members of Master P's No Limit Soldiers, feuding with the West Texas Rednecks. At The Great American Bash, they defeated Rednecks members Curt Hennig and Bobby Duncum, Jr. in a tag team match. At Bash at the Beach, they defeated Rednecks in a four-on-four Elimination tag team match when Mysterio pinned Hennig. After Master P's departure from WCW, Mysterio formed a stable with Eddie Guerrero and Billy Kidman known as the Filthy Animals. The three wrestlers soon began a feud with the Dead Pool. The Filthy Animals defeated the Dead Pool in a six-man tag team match at Road Wild and at Fall Brawl. On the August 19 edition of Thunder, he lost the Cruiserweight Title to Lenny Lane. Konnan later joined the group. Then Mysterio and Konnan teamed up together on October 18 edition of Nitro to defeat Harlem Heat for the World Tag Team Championship. Mysterio, however, was injured during the match and was sidelined due to injury. Billy Kidman substituted for Mysterio and teamed with Konnan during their title defense against Harlem Heat and The First Family, in which Filthy Animals went on to lose the title back to Harlem Heat.
Mysterio returned in the spring of 2000 and remained a steady performer, eventually joining the New Blood faction in early 2000 opposing the Millionaire's Club. On the August 14 edition of Nitro, Mysterio and Juventud defeated The Great Muta and Vampiro to win the World Tag Team Championship. They were stripped of the title, however, after Ernest Miller pinned Disco Inferno with the stipulation that if he pinned Disco, Mysterio and Guerrera would be stripped of the title. The Filthy Animals then feuded with the Natural Born Thrillers in the fall of the year. At Fall Brawl, the Filthy Animals fought the Thrillers to a no contest in an Elimination tag team match. Mysterio reformed his tag team with Kidman and the two challenged for the World Tag Team Championship in a Triangle match at Halloween Havoc, facing the champions Natural Born Thrillers and the Boogie Knights, where the Thrillers retained.
At Mayhem, the duo defeated Alex Wright and KroniK in a 3-on-2 handicap match after KroniK left the ring and abandoned Wright. Konnan, Kidman and Mysterio feuded with Jeff Jarrett and Harris Brothers, which culminated in a Bunkhouse Street Fight at Starrcade, won by Jarrett's team. In the beginning of 2001, the Filthy Animals feuded with Team Canada, to whom they lost in a Penalty Box match at Sin. At SuperBrawl Revenge, Mysterio unsuccessfully challenged Chavo Guerrero, Jr. for the Cruiserweight Title. Kidman and Mysterio participated in a Cruiserweight tag team tournament for the newly created WCW Cruiserweight Tag Team Championship and advanced to the final round where they ended up losing to Elix Skipper and Kid Romeo. On the March 26 (and the final) edition of Nitro, they defeated Skipper and Romeo in a rematch to win the Cruiserweight Tag Team Titles before WCW was sold to the World Wrestling Federation (WWF).
In June 2002, Mysterio signed with World Wrestling Entertainment (WWE), and promos were aired hyping his debut simply as Rey Mysterio. Mysterio made his WWE debut on the July 25, 2002 edition of SmackDown! as a fan favorite in a match against Chavo Guerrero, which Mysterio won. Soon after, he joined John Cena and Edge to feud with The Un-Americans. He eventually began feuding with Kurt Angle, which culminated in a match at SummerSlam that Angle won after forcing Mysterio to submit to the ankle lock. He then formed a tag team with Edge; the two participated in a tournament for the newly created and SmackDown!-exclusive WWE Tag Team Championship. They lost to Kurt Angle and Chris Benoit in the finals of the tournament at No Mercy.
After they failed in winning the title, Mysterio and Edge defeated Los Guerreros in a number one contender's match on the October 24 edition of SmackDown! to earn a title shot. On the November 7 edition of SmackDown!, they defeated Angle and Benoit in a two out of three falls match to win their first Tag Team Championship. They were the shortest reigning champions in the title's history with a reign of 12 days as they lost the tag titles to Los Guerreros in a Triple Threat Elimination match that also involved former champions Angle and Benoit at Survivor Series. After losing the title, Edge and Mysterio went their separate ways to focus on their singles careers.
On March 6, 2003 edition of SmackDown!, Mysterio defeated Tajiri and Jamie Noble in a Triple Threat match to earn a shot at the WWE Cruiserweight Championship. At WrestleMania XIX, he challenged the champion Matt Hardy for the title but lost after Shannon Moore interfered. He then had a short feud with The Big Show, culminating in a match at Backlash, which Show won. On the May 22 edition of SmackDown!, Mysterio defeated Shannon Moore and Crash Holly in a Handicap Elimination match to become the number one contender to the Cruiserweight title. On the June 5 edition of SmackDown!, he defeated Hardy to win the Cruiserweight Championship. He defended the title on a regular basis, before he lost the title to Tajiri on the September 25 edition of SmackDown!. They both feuded with each other and had a rematch for the title at No Mercy, where Tajiri cheated to retain his title.
On the January 1, 2004 edition of SmackDown!, Mysterio defeated Tajiri to win his second Cruiserweight Championship. After a successful title defense against Jamie Noble at Royal Rumble, Mysterio lost the title to Chavo Guerrero at No Way Out. At WrestleMania XX, Mysterio took part in a Cruiserweight Open for the title, but lost as Chavo retained the title. On the March 18 edition of SmackDown!, he won a Gauntlet match to earn a shot at the WWE Championship against the champion Eddie Guerrero. Later that same night, he lost to Guerrero in the main event for the WWE Title.
At Judgment Day, Mysterio teamed with Rob Van Dam and defeated the Dudley Boyz. On June 17 edition of SmackDown!, he defeated Chavo Classic for a record-setting eighth Cruiserweight Championship and Mysterio's third Cruiserweight Title in his WWE career. He successfully defended the title against Classic's son Chavo Guerrero at The Great American Bash. While Mysterio was Cruiserweight Champion, Spike Dudley turned into a villain after plowing Mysterio through a table and joined the other Dudleys before winning the Cruiserweight Title from Mysterio on the July 29 edition of SmackDown!. At Survivor Series, he participated in a Fatal Four-Way match for the Cruiserweight Title involving the champion Spike, Chavo Guerrero and Billy Kidman. Mysterio lost when Dudley pinned Guerrero to retain.
After an unsuccessful attempt at regaining the Cruiserweight Title, Mysterio formed a tag team with Rob Van Dam, and went on to win the Tag Team Championship from Kenzo Suzuki and René Dupreé on the December 9 edition of SmackDown!. They successfully defended the title against the former champions at Armageddon, before losing the title to the Basham Brothers on the January 13, 2005 edition of SmackDown! after Van Dam was injured. Mysterio then teamed up with Eddie Guerrero to win the Tag Team Championship back from the Bashams at No Way Out. In a departure from traditional booking, the new champions did not defend their title at WrestleMania 21, but instead had a match against each other which Mysterio won.
This match led to a storyline in which Guerrero turned into a villain and beat him up after abandoning him during a rematch against MNM for the Tag Team Championship. Then after a no disqualification match against Chavo, Eddie came out and hit a brainbuster on the steel steps, which left Mysterio lain on the floor due to Eddie becoming increasingly frustrated that he could not beat Mysterio. Guerrero and Mysterio continued to feud, with Guerrero threatening to reveal a secret he and Mysterio shared involving Mysterio's real-life son Dominic (actually spelt Dominik), unless Mysterio deferred to Guerrero's authority. Guerrero later revealed that, in the storyline, he was Dominic's biological father. The storyline went that Guerrero knew Mysterio was having trouble starting his own family, so Guerrero left Dominic as a baby with Mysterio and his wife Angie to raise. In subsequent weeks, Guerrero threatened to take custody of Dominic, drawing up custody papers and having his lawyer present them to Mysterio. At SummerSlam, Mysterio defeated Guerrero in a ladder match for the custody of Dominic. Mysteriro engaged in a brief feud with John "Bradshaw" Layfield with JBL eventually coming out the victor at No Mercy. On November 13, 2005, Eddie Guerrero was found dead in his hotel room in Minneapolis, Minnesota. That same day at a WWE "Super Show" where SmackDown! and Raw were both taped, Mysterio gave an emotional speech about Eddie, and in a show of respect removed his mask (though he put his head down, so no one could see his face). Mysterio went on to defeat Shawn Michaels in an interpromotional match later that night. After the match, Michaels and Mysterio hugged in the ring and Mysterio pointed up to the sky, crying, in memory of Guerrero.
Mysterio participated in the main event of Survivor Series as part of Team SmackDown! along with Randy Orton, Bobby Lashley, Batista and JBL who defeated Team Raw (Shawn Michaels, Kane, The Big Show, Carlito, and Chris Masters). After Survivor Series, Mysterio faced Big Show in a match billed as "David vs. Goliath" in a SmackDown! special show. The match stemmed from Mysterio eliminating Big Show at Survivor Series, and ended as a "no contest" when Big Show's tag team partner Kane interfered in the match. Mysterio continued to feud with Raw's World Tag Team Champions, even finding a tag team partner in World Heavyweight Champion Batista who, along with Mysterio, would be set to face Raw's Kane and The Big Show in a tag match at Armageddon. Before Armageddon, Batista and Mysterio defeated Mysterio's longtime rivals MNM on December 19 edition of SmackDown! to win the Tag Team Championship in a match they both dedicated to Eddie Guerrero. Now the Tag Team Champions, Mysterio and Batista's match with Big Show and Kane was billed as "Champions vs. Champions." At Armageddon, Mysterio and Batista lost this "Raw vs. SmackDown!" match when Kane pinned Mysterio after a chokeslam. On December 30 edition of SmackDown!, MNM invoked their rematch clause, defeating Batista and Mysterio with help from the returning Mark Henry to regain the Tag Team Championship after an assault on Batista by Henry. Mysterio and Batista lost a Steel Cage match in an effort to reclaim the titles the following week, again courtesy of interference by Henry.
At Royal Rumble, Mysterio won the 2006 Royal Rumble match after entering at the number two spot and lastly eliminating Randy Orton to win the match. By winning the Royal Rumble, Mysterio earned a World Heavyweight title shot at WrestleMania 22. By lasting over sixty-two minutes in the match, Mysterio also set a Royal Rumble record for longevity and size. Mysterio dedicated his performance at the Royal Rumble to Eddie Guerrero. After his win, he was congratulated by Chris Benoit, Dean Malenko, Chavo Guerrero and Rob Van Dam - all close friends and family of Eddie.
During the February 3, 2006 episode of SmackDown!, an upset Orton interrupted Mysterio's victory speech, challenging Mysterio to a match for his WrestleMania world title shot. As Mysterio looked upward for guidance on this decision, Orton verbally attacked him and the memory of Guerrero, saying "Eddie ain't in heaven, Eddie's 'down there' - IN HELL!" Mysterio proceeded to attack Orton and later accepted the challenge. Orton defeated Mysterio at No Way Out after illegally using the ropes to get the pin. On the next edition of SmackDown!, however, General Manager Theodore Long added Mysterio to the title match, making it a Triple Threat match for the World Heavyweight title. At WrestleMania 22, Mysterio defeated Orton and then-World Heavyweight Champion Kurt Angle, pinning Orton to win his first World Heavyweight Championship.
On the April 7 edition of SmackDown!, Mysterio - who was billed as being an "underdog champion" - made his first successful World Heavyweight title defense against Randy Orton. Mysterio went on to retain his title again during a WrestleMania rematch on SmackDown! against Kurt Angle, three weeks later. The week before the title defense took place saw the start of a feud between the then-United States Champion John "Bradshaw" Layfield and Mysterio. The rivalry kicked off after JBL stated he deserved the World Heavyweight title during his celebration of becoming the U.S. Champion. The feud with JBL saw Mysterio face off against any opponent of JBL's choosing in the three weeks leading up to his title match against Mysterio at Judgment Day. Mysterio was defeated by Mark Henry and The Great Khali in separate non-title matches before wrestling Kane to a "no contest". Mysterio retained his title against JBL at Judgement Day. The feud intensified when JBL lost the U.S. Title to Bobby Lashley five days later on SmackDown! after being tricked by Mysterio to take on all comers like he had. This led JBL to vow that if he did not win his rematch against Mysterio, he would quit SmackDown!. In the main event of the evening, Mysterio won and retained the World Heavyweight Championship, causing JBL to (kayfabe) leave SmackDown!, until ECW One Night Stand, when JBL announced he would return as a color commentator.
It was revealed that Mysterio would have to defend his title against ECW wrestler Sabu at One Night Stand. In the weeks leading up to his title defense, Mysterio defeated Cruiserweight Champion Gregory Helms in a Champion vs. Champion match but was defeated by Rob Van Dam at WWE vs. ECW Head to Head on June 7. At One Night Stand, Mysterio (who was wearing a mask with the letters "ECW" written on the back, despite being a fan favorite was booed by ECW fans) retained his title in a match after he and Sabu were ruled unable to continue following a triple jump DDT through a table from Sabu.
Mysterio later defeated Mark Henry for Mysterio's title, after Chavo Guerrero came to the ring as the referee was down and hit Henry with a steel chair. When the referee regained consciousness, Mysterio had used a trick of Eddie Guerrero's and pretended to be knocked out and left the challenger holding the chair and eventually won via disqualification. Mysterio then feuded with King Booker after Booker won a battle royal to become the number one contender for the World Heavyweight Championship. Booker attacked Mysterio from behind backstage with the help of Booker's wife Queen Sharmell. The next week on SmackDown!, Mysterio gained revenge by attacking Booker and his "court". This rivalry continued for several weeks and saw Mysterio defeating Booker's court member William Regal on an edition of SmackDown!, moments before attacking the challenger and hitting him with a 619 around the steel post. On the July 15, 2006 edition of Saturday Night's Main Event, Mysterio defeated Booker in a six man tag match and again days later on SmackDown! in singles action. At The Great American Bash, Mysterio lost the World Heavyweight Championship to Booker after Chavo Guerrero turned on Mysterio and hit him with a steel chair, and also cost him his rematch at SmackDown!. Then on an edition of SmackDown!, Guerrero challenged Mysterio to an "I Quit" match. In that match, Chavo injured Mysterio's knee, causing him to take time off wrestling.
Mysterio made his in-ring return at SummerSlam, defeating Guerrero with the 619, after Guerrero obsessed over Mysterio's return as well as wanting to injure Mysterio again. On the August 31 edition of SmackDown!, Mysterio won a "Championship Competition" to become the number 1 contender for the World Heavyweight Championship, defeating Batista and Finlay. On the September 7 edition of SmackDown!, Mysterio had an "I Quit" match with Chavo Guerrero, which he won after hitting Guerrero's knee with a chair repeatedly in a similar manner to which Mysterio had been put out of action. Mysterio then began a feud with The Great Khali, which would lead to a match at Unforgiven where he would face Khali for the World Heavyweight Championship (the match was eventually made a Triple Threat match involving Batista), but was unsuccessful in recapturing the title.
Mysterio then began a feud with Finlay, an opponent chosen by JBL. The rivalry was marked as "Fight vs. Flight", a competition between the two contrasting fighting styles of both wrestlers - Finlay's physicality, versus the high-flying Mysterio. On October 28, after fighting to a "no contest" at No Mercy, followed by a double-disqualification in a number one contender's match for Batista's World Heavyweight title on the next SmackDown! (The Undertaker would succeed the pair), he defeated Finlay in a Stretcher match at Cyber Sunday. During this feud, he conceded one match to Finlay on an episode of SmackDown! and was part of the winning team at Survivor Series which consisted of both wrestlers on opposing sides (although Mysterio was second to be eliminated). The rivalry was brought to an abrupt end when Finlay was placed in a feud with The Great Khali stemming from that same pay-per-view.
Mysterio then began a feud with Montel Vontavious Porter(MVP) by expressing his disdain over MVP's actions towards his former tag team partner and number one contender for his U.S. Championship title, Matt Hardy. Mysterio was granted a title match at Armageddon, which he won via countout, though he was unable to claim the belt due to the stipulations of the match. He then re-entered the world title picture when he emerged as victor of the Beat the Clock challenge for the chance to face the World Heavyweight Champion Edge at Royal Rumble. However, he was unsuccessful in winning the championship. WWE.com announced on February 14 that Mysterio suffered a biceps injury during an overseas tour. Despite the injury, Mysterio faced Edge for the title again at No Way Out. On the February 22 edition of SmackDown!, Mysterio announced that his injury would keep him out of action for at least six months, and he eventually underwent three surgeries within the space of a month.
Mysterio made his return on the June 23 episode of Raw, as Mysterio was the first superstar to be drafted in the 2008 WWE Draft from the SmackDown brand to the Raw brand. On the June 30 edition of Raw, Mysterio came to make an announcement to all the Raw fans which led to a minor fight with Santino Marella. Mysterio made his Raw in-ring debut the next week, pinning Marella after a 619.
General Manager Mike Adamle announced on Raw that John Cena was injured and that his replacement in the Championship Scramble at Unforgiven was Mysterio. The next week, Mysterio made his return to Raw after an extended absence by attacking Kane, turning back numerous claims that Kane had "ended his career". Mysterio then made his in-ring return at Unforgiven, competing in the Raw Championship scramble match. Later, Mysterio accepted John "Bradshaw" Layfield's (JBL) challenge for Layfield's Intercontinental Championship at WrestleMania XXV, which Mysterio won in 21 seconds after connecting with the 619. With this win, Mysterio became the twenty first Triple Crown Champion in WWE history.
Mysterio was drafted back to SmackDown! during the 2009 WWE Draft on the April 13 episode of Raw, in the process making the Intercontinental Title exclusive to SmackDown for first time since Chris Benoit held the title in mid-2002. He then began a long-time feud with Chris Jericho, resulting in Mysterio defending and retaining his title at Judgment Day. At Extreme Rules, Jericho managed to unmask Mysterio and pin him for the Intercontinental Championship, however his face was never shown, as he covered it. As a result, Mysterio and Jericho were booked in a Title vs. Mask match at The Bash, in which Mysterio was victorious after tricking Jericho with a second mask. On August 2th, WWE announced on that Mysterio would be suspended for 30 days, effective September 2, for violating the company's Wellness Policy. In an interview with Mexican newspaper Record, Mysterio stated that he was suspended for a drug he was using for his knee and arm. Mysterio stated that he had a prescription for the drug, but was unable to produce it in time to prevent his suspension due to being on vacation and doing a promotional tour. On the September 4 episode of SmackDown (taped on September 1), Mysterio lost the Intercontinental Championship to John Morrison.
Mysterio returned from his suspension at Hell in a Cell to face Chris Jericho and The Big Show for the Unified Tag Team Championship title with former tag team partner Batista, but they failed to win the title after Mysterio was pinned by Big Show. At Bragging Rights, Mysterio was unsuccesful in winning the World Heavyweight Championship. In that Fatal Four-Way with Batista, CM Punk and the champion The Undertaker, Mysterio broke up Batista's pin on Undertaker after a Batista Bomb leading to Batista losing his temper. After the match, he attacked Mysterio. This led to Batista entering into a dramatic change of attitude, stretching into an ongoing storyline in which Batista turned heel. Mysterio was booked at match at Survivor Series with Batista. At Survivor Series, Batista destroyed Mysterio, saying that Rey will be spending his Thanksgiving in the hospital. He reurned on December 18, defeating Batista and is going to face Undertaker on Christmas night.