In March 2000, Guerrero began pursuing the affections of Chyna, who he referred to as his "Mamacita". Chyna initially rejected his advances, but allied with him following WrestleMania 2000, declaring that she could not resist his "Latino Heat." Guerrero won his first WWF title on the April 3, 2000 edition of Raw is War by defeating Chris Jericho for the WWF European Championship with help from Chyna. After Chyna abandoned Lita to be attacked by the Dudley Boyz, he and Chyna began a feud with Essa Rios and Lita, ending in a European title defense at Backlash, which was also billed as the night of Guerrero's prom (he was said to have just earned a GED). Guerrero defeated Rios after arriving at ringside in a 1957 Chevrolet, even wrestling in his tuxedo pants and a bow tie. Guerrero successfully retained the title against former Radicalz friends Saturn and Malenko in a Triple Threat match at Judgment Day, before finally losing the title to Saturn at Fully Loaded.
Over the next few months, friction began to build between Guerrero and Chyna. Chyna was upset when Guerrero pinned her to advance in the King of the Ring tournament. At SummerSlam, Chyna won the WWF Intercontinental Championship in a mixed tag match. They had also inserted themselves in the drama between Triple H, Stephanie McMahon, and Kurt Angle. Guerrero claimed to not mind and then begged Commissioner Mick Foley to let him take part in a title defense between Chyna and Angle on the September 4 edition of Raw is War, claiming he was afraid that Angle would injure Chyna. After Angle knocked Chyna down with the title belt, Guerrero "accidentally" pinned her to win his first Intercontinental Championship while trying to revive her. Chyna became visibly uncomfortable as Guerrero began to cheat in order to retain his title, while Guerrero was upset that Chyna was posing for Playboy magazine, even trying to invade the Playboy Mansion to stop the shooting. Just when it appeared that Chyna would leave Guerrero, he proposed to her and she accepted. At Unforgiven, Chyna helped Guerrero in retaining his title against Rikishi. The engagement was called off when Guerrero was caught showering with two of The Godfather's hos (one was Victoria) claiming that "Two Mamacitas are better than one!"
Guerrero turned into a villain as a result of the incident. Then, the Radicalz reunited and feuded with the reformed D-Generation X (Chyna, Billy Gunn, Road Dogg, and K-Kwik). They defeated DX at Survivor Series in an elimination tag team match and assisted Triple H in his match with Stone Cold Steve Austin. Guerrero was later defeated by Gunn for the Intercontinental Championship, with help from Chyna. At Rebellion, Guerrero and Malenko lost to Gunn and Chyna. Benoit left the group to focus on a singles career while the rest of the Radicalz feuded with Lita and the Hardy Boyz (Matt and Jeff). At Armageddon, the Radicalz defeated the Hardyz and Lita in an elimination tag team match.
In early 2001, Guerrero feuded with Chris Jericho, Benoit, and X-Pac over Jericho's Intercontinental Championship. At No Way Out, the four men faced each other in a Fatal Four-Way match, which Jericho won. Guerrero focused on the European Championship, feuding with the champion Test defeating him at WrestleMania X-Seven to win his second European Championship with help from Saturn and Malenko. In April, Radicalz feuded with Test and his partners. Guerrero eventually left the Radicalz, siding with the Hardy Boyz and Lita. At this point, Guerrero developed an addiction to pain medication stemming from his 1999 car accident and in May 2001 was sent to rehab. To explain his absence, a storyline was created where Guerrero was "injured" by Prince Albert in a match. On November 9, 2001, he was arrested for drunk driving and was subsequently released by the WWF three days later.
Guerrero returned to WWF on the April 1, 2002 edition of Raw, attacking Rob Van Dam. He feuded with Van Dam defeating him for his second WWF Intercontinental Championship at Backlash. After retaining the title against Van Dam at Insurrextion and Judgment Day, he finally lost the belt to Van Dam on the May 27 episode of Raw in a ladder match although a drunk fan jumped in the ring knocking down the ladder that Guerrero was climbing caused both Guerrero and Van Dam to think up some new moves to continue the match without any mistakes. Guerrero then feuded with Steve Austin, but Austin left WWE before a match could take place. Chris Benoit returned to WWE the night Guerrero lost the title and reunited with him. Guerrero and Benoit feuded with Ric Flair for a while and Guerrero even lost a match to Flair at King of the Ring. Guerrero lost a match to The Rock, challenging him for the WWE Undisputed Championship after The Rock sang a version of "La Bamba" with the words changed to insult Guerrero on the July 29 edition of Raw.
On August 1, 2002, Guerrero and Benoit began to wrestle exclusively for WWE's SmackDown! brand. Guerrero feuded with Edge, to whom he lost at SummerSlam. Eddie continued his feud with Edge, whom he defeated at Unforgiven; they then had a No Disqualification match two weeks after Unforgiven on SmackDown which Edge won thus ending the rivalry. With Benoit focusing on Kurt Angle, Guerrero aligned himself with his nephew Chavo, forming the tag team Los Guerreros. In contrast to a previous WCW storyline with his nephew, Chavo fully agreed with his uncle as their slogan stated "We lie, we cheat, and we steal, but at least we're honest about it." In order to push the new tag team, vignettes were produced, which included things such as the two finagling their way into a rich lady's house and throwing a pool party.The duo entered the eight-team tournament for the new WWE Tag Team Championship, sneaking past Rikishi and Mark Henry in the opening round, before starting a feud with the newly formed tag team of Kurt Angle and Chris Benoit. In one of the team's definitive moments, Chavo told Benoit that his former friend Guerrero was assaulted by his tag team partner Angle. Benoit ran to make the save, only to have himself locked inside a room. Guerrero then appeared in the room and assaulted Benoit with a steel chair. Benoit and Angle managed to overcome their differences and eventually defeated Los Guerreros in the tournament semi-finals. Later on, Benoit and Angle won the title. Benoit and Angle then fought for a trophy for being the first WWE Tag Team Champion. Much to Benoit's surprise, Los Guerreros helped him win the match.At Survivor Series, Los Guerreros faced the new champions Edge and Rey Mysterio and the team of Angle and Benoit for the title. Eddie made Mysterio submit to The Lasso From El Paso to win their first WWE Tag Team Championship. They were defeated by Team Angle (Charlie Haas and Shelton Benjamin) on the February 6, 2003 edition of SmackDown!. Los Guerreros and Team Angle began feuding with each other. Los Guerreros participated at WrestleMania XIX as contenders for the Tag Team Title, along with the team of Benoit and Rhyno. Both teams lost to Haas and Benjamin in a Triple Threat match. At Backlash, Los Guerreros lost to Team Angle in a rematch.
Five days prior to Judgment Day, Chavo tore his biceps, forcing Eddie to look for another partner. He chose Tajiri. They won the WWE Tag Team Championship, Guerrero's second and Tajiri's first at Judgment Day by defeating Team Angle in a ladder match. The following week, Guerrero and Tajiri managed to retain their title by cheating. In addition, they also defeated Roddy Piper and his protegè Sean O'Haire in Madison Square Garden. After Guerrero and Tajiri lost the title to Team Angle on the July 3 edition of SmackDown!, Guerrero turned on Tajiri, slamming his partner through the windshield of his low-rider truck.
In July 2003, Guerrero competed in a tournament for the United States Championship. He managed to advance to the final round, defeating Último Dragón and Billy Gunn in the process, where he would meet Chris Benoit. At Vengeance, Guerrero turned to his cheating tactics, hitting Benoit with the belt at one point in the match. Guerrero tried to get Benoit in trouble by placing the title belt on top of the unconscious Benoit. It did not work, however, since he knocked out the referee earlier with a belt shot to the kidneys. The match ended with interference and a Gore from Rhyno, Benoit's own partner, who was furious at the team's failure. Guerrero himself said that this was a major point in the character of Latino Heat, since he himself realized that the fans wanted to see him lie, cheat, and steal. Guerrero pinned Benoit and won the WWE United States Championship.At SummerSlam, Guerrero retained his title by defeating Rhyno, Benoit, and Tajiri in a Fatal Four-Way match. He turned face again by engaging in a rivalry with John Cena. On the September 11 edition of SmackDown!, Guerrero challenged Cena to a "Latino Heat" Parking Lot Brawl match for the United States Championship, which Guerrero won with help from his returning nephew, Chavo. The next week, Los Guerreros defeated The World's Greatest Tag Team (previously Team Angle) to win the WWE Tag Team Championship for a second time, although it was Eddie's third reign. Guerrero thus held the WWE United States Championship and one-half of the WWE Tag Team Championship concurrently.Guerrero engaged in a feud with The Big Show, which involved Guerrero giving the Big Show some laxative laced burritos and then later spraying the Big Show from a sewage truck. The feud ended when Guerrero dropped the United States title to Big Show at No Mercy. Four days later, Los Guerreros lost the Tag Team Championship to The Basham Brothers (Doug and Danny). They began feuding with The Basham Brothers, but failed to regain the titles at Survivor Series. As Los Guerreros attempted to regain the tag team title, things began to go downhill between Chavo and Guerrero and animosity began to build. Chavo then attacked and turned on Eddie after he suffered a beating from The Bashams. Guerrero feuded with Chavo and defeated him at the Royal Rumble to settle their feud.
When Chris Benoit defected to Raw after winning the Royal Rumble, using his title shot to go for Triple H's World Heavyweight Championship, Eddie won a 15-man Royal Rumble style match on the January 29, 2004 edition of SmackDown! to earn a shot at the WWE Championship. After becoming the number one contender, Guerrero elevated himself to main event status and began feuding with the WWE Champion Brock Lesnar. At No Way Out, Guerrero defeated Lesnar in the main event to win the WWE Championship. His next feud was with Kurt Angle, whom he defeated at WrestleMania XX to retain his title in his first big defense. At the end of this event, Guerrero celebrated in the ring with longtime friend Chris Benoit, who had just won the World Heavyweight Championship.
In March, he started a feud with fellow Texan John "Bradshaw" Layfield (JBL) after JBL interrupted Eddie's match with Booker T. At Judgment Day, Guerrero defended his WWE title against JBL and retained the title after getting himself disqualified because JBL had kayfabe given his mother a heart attack. At The Great American Bash, Guerrero defended the title against JBL in a Texas Bullrope match. JBL won after Angle (who was General Manager of SmackDown! at the time) reversed the decision after Guerrero appeared to have retained the title. On the July 8 edition of SmackDown!, Guerrero pulled a switcharoo with Shannon Moore, who was wrestling as "El Gran Luchadore" and wore the costume. The next week on SmackDown!, Guerrero faced JBL in a steel cage match for the WWE title where El Gran Luchadore appeared again and cost Guerrero the match; he later revealed himself as Kurt Angle. Guerrero continued his feud with Angle again.
At SummerSlam, Guerrero lost to Angle after submitting to his ankle lock. Guerrero then allied himself with the Big Show. Each week Angle and his new allies Luther Reigns and Mark Jindrak began targeting Guerrero and Big Show. Guerrero defeated Reigns in a singles match at No Mercy. General Manager Theodore Long booked a Survivor Series Elimination match between a team led by Guerrero and a team led by Angle. Guerrero's team consisted of himself, Big Show, John Cena (replacing the originally chosen Rey Mysterio), and Rob Van Dam. At Survivor Series, Guerrero's team defeated Angle's team. Guerrero, along with Booker T and The Undertaker, then challenged JBL for a WWE Championship rematch. Along the way, Guerrero found a partner in Booker T. At Armageddon, Guerrero and Booker's initial teamwork broke away, and the match ended with JBL pinning Booker following the Clothesline From Hell. Afterwards, Guerrero and Booker briefly and unsuccessfully attempted to win the Tag Team Championship.
At No Way Out, Eddie teamed up with longtime friend and sometimes rival, Rey Mysterio and defeated The Basham Brothers to win his final title, the WWE Tag Team Championship for a fourth time, with it being Mysterio's third reign. Many expected the new champions to defend their title at WrestleMania 21, but after encouragement from Chavo, Guerrero challenged Mysterio to a one-on-one match instead so they could "bring the house down." The two wrestled a match at WrestleMania with Mysterio getting the win. Although visibly frustrated, Guerrero congratulated his partner. After several mishaps in the weeks following WrestleMania, the growing tension between Guerrero and Mysterio finally erupted when they lost their tag team championship to the new team MNM (Johnny Nitro and Joey Mercury) on the April 21 edition of SmackDown!. Although the next week they received a rematch to regain the title, Guerrero turned heel once again by abandoning his partner, whom he had considered "his family" earlier in the show.
At the end of one episode of SmackDown!, he attacked his former tag team partner, Mysterio, leaving him bruised and bloody after suplexing him onto a set of steel steps. Guerrero, having turned heel, then adopted a new, somewhat sociopathic gimmick. During this time, he also stopped driving his low-riders down the ring and walked to the ring with a frown on his face, and reverted to using the Lasso from El Paso as his finishing move. At Judgment Day, Guerrero lost to Mysterio by disqualification after hitting Mysterio with a chair.
On the June 30 edition of SmackDown!, Guerrero threatened to reveal a secret about Mysterio and his son Dominick. The storyline grew to involve the families of both men, with both sides pleading for Guerrero not to reveal the secret. Mysterio defeated Guerrero again at The Great American Bash, a match with a stipulation that if Guerrero lost, he would not tell the secret. Yet Guerrero revealed the secret anyway on the following episode of SmackDown! - telling Dominick and the audience that Guerrero was his real father. In the following weeks, Guerrero revealed the details of the secret in a series of what he called "Eddie's Bedtime Stories." During that time he now had a dark comical gimmick. He claimed that he had a child out of wedlock (Dominick) while his marriage was going through hard times. He claimed he then allowed Mysterio and his wife, who were "having trouble conceiving", to adopt the child as their own. At SummerSlam, Guerrero lost a ladder match over Dominick's custody to Mysterio. Their feud ended when Guerrero gained a victory over Mysterio in a steel cage match.
Following his feud with Rey Mysterio, Guerrero was named number one contender to the World Heavyweight Championship and given a title match with Batista. Despite this, Guerrero quickly proclaimed himself to be Batista's friend. Batista was wary of Guerrero, however, and a series of matches with MNM only supported his suspicions, as Guerrero appeared to have reverted to his cheating ways. In response to Batista's suspicions, Guerrero helped Batista win a match against his tag team partners, John "Bradshaw" Layfield and Christian. Batista defeated Guerrero at No Mercy to retain the World Heavyweight Championship. During the match, Guerrero struggled with a decision about whether or not to use a steel chair to secure the victory, eventually opting not to use it and losing as a result. Though the two demonstrated mutual respect after the match, Guerrero seemed displeased by the loss. Guerrero told Batista that he realized how low he had sunk since losing the WWE Championship in 2004, having attacked his best friend Rey Mysterio. Guerrero told Batista that shaking his hand at No Mercy had returned his respect to him. This turned Guerrero face again.Guerrero wrestled his final match on the November 11 edition of SmackDown!, defeating Mr. Kennedy to qualify for a place on the SmackDown! team at the Survivor Series, but died before he could participate at the pay-per-view. Randy Orton was named as the official replacement for Guerrero on the team.