Eugene, the "mentally challenged" nephew of Raw General Manager Eric Bischoff, was placed in the care of Regal during his return to WWE. He became friends with Eugene, becoming a fan favorite in the process. Regal was ordered by Bischoff to make Eugene lose so that he would leave WWE, but his friendship with Eugene caused him to try only half-heartedly to cost Eugene his match with Robert Conway. Despite this, Bischoff put Regal back on the active roster. Regal would later team with Eugene and win the World Tag Team Championship from La Résistance on the November 15, 2004 edition of Raw. Eugene legitimately injured himself at New Year's Revolution after botching a dropkick. This ultimately cost them the World Tag Team Championship, as Regal unsuccessfully attempted to defend the titles with announcer Jonathan Coachman as Eugene's stand in. The pair wrestled and lost a match against La Résistance at a house show, crowning them with their third reign. On February 4, 2005, Regal and old ally Tajiri defeated La Résistance to win the World Tag Team Championship on an episode of Raw, broadcast live from Tajiri's home country Japan. La Résistance entered in a feud with the champions, and repeatedly missed out on the titles during matches, mainly on Sunday Night Heat. During their last shot for the titles, La Résistance thought they had won back the titles, only to have the decision reversed by referee Mike Chioda due to the legal man not being pinned. After winning this match, an open challenge to any tag team was issued by Regal to try and win their belts. On the following episode of Raw, Regal and Tajiri successfully defended the belts against the debuting Romeo and Antonio, known collectively as "The Heart Throbs." At Backlash in May, Regal and Tajiri participated in a Tag Team Turmoil match in which four teams competed for the World tag team titles. Regal and Tajiri were eliminated by La Résistance who, in turn, were eliminated by Hurricane and Rosey, who became the new champions. Shortly before the 2005 ECW One Night Stand, Regal announced that he was joining Eric Bischoff's anti-ECW faction to invade the pay-per-view, and told Tajiri he had to make a choice, either to join with Regal or join with ECW. Tajiri responded by chanting, "EC-Dub! EC-Dub!" (the traditional ECW chant). Regal did indeed invade the ECW pay-per-view, along with many other WWE performers.
On June 30, 2005, Regal was sent to SmackDown! as part of an eleven person trade during the draft. His first match on SmackDown! was on July 7 against Matt Morgan, in what was to be Morgan's final WWE match. It was interrupted before Regal was even able to enter the ring by The Mexicools. His first full match as part of the roster was a loss to Chris Benoit in a chain wrestling match on the July 16 episode of WWE Velocity. Having applied the Regal Stretch which Benoit managed to escape from, Regal eventually submitted to the Crippler Crossface.
On August 4, 2005, Regal was scheduled to go one on one with Scotty 2 Hotty, but the Mexicools came in and attacked both men. Two weeks later, they teamed up on SmackDown! against Psicosis and Super Crazy with Juventud in their corner. Halfway through the match, Regal betrayed Scotty by refusing to tag him and walked out of the ring with a smirk on his face, allowing the Mexicools to pick up the win. Two days later, Regal cut a promo telling the crowd that he had returned to his former self, referring to himself as a "scoundrel" and a "rogue". The promo ended when Scotty ran to the ring and attacked Regal. The following week, a match between the two was cut short when another Englishman, the debuting Paul Burchill, interfered to aid his countryman. Regal went on to take Burchill under his wing and tag with him on the hunt for the WWE Tag Team Championship, but the teams biggest exposure was a loss in a handicap match against Bobby Lashley at Armageddon.
On the February 3 edition of SmackDown!, Regal and Burchill told the "network representative" Palmer Canon that they no longer wanted to be a tag team so they could go their separate ways. During this discussion, Burchill informed Canon that his family heritage traced back to the pirate Blackbeard, and that he wanted to turn this into a pirate gimmick. Burchill, with this heroic persona, started a rivalry with former team mate Regal, who would try to convince Burchill to return to his ruthless ways. Regal faced Burchill, his first match as a pirate, and was defeated following Birchill's Walking the Plank move. Burchill once again defeated Regal in a match with the stipulation that Regal would have to dress like a "buxom wench" if he lost the match. Lady Regal, as SmackDown! announcers jokingly referred to him, had no choice but to dress up like this until Burchill lost a match. This stipulation ended after Burchill abandoned Regal during a match that saw Regal and Burchill defeated by the Gymini tag team.
Regal continued to wrestle in a lower mid-card status, the highlight of which saw Regal turn face for one night only as he faced the then-reigning United States Champion, JBL in a losing effort while in England. Soon after Booker T became King Booker after becoming King of the Ring and Regal joined King Booker's Court, playing the role of a town crier. As a member of the Court, Regal helped Booker in his feud against Bobby Lashley, occasionally teaming up with fellow Court member Finlay in tag team matches. However, during this time, Regal also feuded with Finlay for the WWE United States Championship. Regal was knighted by King Booker and changed his ring name to Sir William Regal. At No Mercy, Regal lost to a returning Chris Benoit in a match, turning his back on the King's Court afterwards by knocking down King Booker with a left hand to the face after Booker slapped him and called him useless. During the broadcast, Regal was involved in a backstage segment with Vito in which Vito accidentally exposed his penis for a brief second. WWE.com issued an apology for the incident the next day.
Twelve days after No Mercy, Regal stated that while he had once been one of the world's greatest wrestlers, he had since become a doormat for other SmackDown superstars. He referred to being dressed as a buxom wench for a pirate, the aforementioned locker room incident with Vito, and being knighted by a false king as examples. After announcing he was finished being a whipping boy, he introduced his old tag team partner Dave Taylor, and the two went on to easily defeat the team of Scotty 2 Hotty and Funaki. Though the pair reformed their previous tag team, they did not reuse the Blue Bloods gimmick, instead portraying themselves as sadistic fighters. However, the team was quickly put into jeopardy in their second match together when Taylor suffered a torn meniscus in his left knee leaving him injured. Taylor took a more relaxed role for a couple of weeks as a corner man for Regal and only wrestled in a few short house show matches. Taylor quickly healed from his injury and the pair feuded with WWE Tag Team Champions Paul London and Brian Kendrick. After defeating London and Kendrick on several occasions, at Armageddon, they took part in a 4-way ladder match alongside Johnny Nitro and Joey Mercury and the The Hardys. London and Kendrick coming out on top after Joey Mercury suffered a serious facial injury. On the May 25 edition of SmackDown!, Regal and Taylor competed in a number 1 contenders match for the WWE Tag Team Championship against London and Kendrick, which they lost after Deuce 'n Domino interfered, making both teams the number one contenders. This interference led to a triple threat match the next week on SmackDown!, in which Deuce 'n Domino retained the title.
On June 17, Regal was drafted back to the Raw brand during the Supplemental Draft, ending his tag team with Dave Taylor. On July 2, Regal served as Interim General Manager of Raw, filling in for Jonathan Coachman. While General Manager, Regal introduced the Beat the Clock Sprint to Raw, which was used to determine who would challenge John Cena for the WWE Championship at the 2007 Great American Bash.
On the August 6 edition of Raw, Regal became the new General Manager after winning an over the top rope battle royal featuring other participants from the Raw roster. He began incorporating game shows into Raw while general manager. On the September 3 episode of Raw', Regal was attacked by WWE Champion John Cena in retaliation for rewarding Randy Orton with a WWE title shot after Orton had kicked John Cena's father in the head the previous week. Regal was missing from Raw programming for one month due to this attack, making his return by siding with Vince McMahon. On New Year's Eve, Triple H was scheduled to face Ric Flair, in which Flair's win or retire ultimatum was still active. Regal announced that if Triple H lost the match in any way, he would not participate in the Royal Rumble match at the 2008 Royal Rumble. This was to give Triple H a reason to want to win the match rather than avoid ending the career of his best friend and idol. Regal was scheduled to compete against Hornswoggle that night with Mr. McMahon at ringside. McMahon tossed Regal some brass knuckles during the match and encouraged him to use them on Hornswoggle, but he let Hornswoggle go and left the ring. During the Flair versus Triple H match, Triple H performed the Pedigree on Flair and appeared to be going for the pin when Regal suddenly punched Flair in the face with the brass knuckles. This gave Flair the win by disqualification, ensuring that he could continue to wrestle and that Triple H would not be part of the Royal Rumble. As a result of Regal's actions towards Triple H, the following week on Raw Roulette, Regal lost a First Blood match to Triple H after several right hands to Regal's forehead. A few weeks later, he made the Raw Elimination Chamber match for No Way Out. He later turned face for one night only while on a European tour, by facing Randy Orton in a match to try and teach him some respect.
The following week, Regal won the 2008 King of the Ring Tournament, on a special three hour edition of Raw, where he defeated Hornswoggle, Finlay and CM Punk all by submission. Regal's coronation ceremony the next week was interrupted by the returning Mr. Kennedy. A few weeks later Regal lost a Loser Gets Fired match to Mr. Kennedy, after which, Regal was kayfabe forced to leave WWE. In reality, Regal was suspended on May 20, 2008, for sixty days for his second violation of the company’s Substance Abuse and Drug Testing Policy. On July 28, 2008, Regal returned from his suspension as a "free agent" during an episode of Raw, where he was defeated by then World Heavyweight Champion CM Punk.
Regal began a mini-feud with Jamie Noble after he took an interest in Noble's romantic interest Layla, prompting him to attack Regal. Both men picked up victories in consecutive weeks, before Regal won their third match, departing with Layla at his side. Regal's feud with Noble escalated the subsequent week when Layla declared that Noble was a loser and that she found a man worthy of her in Regal. However, the feud was short lived.
On the November 3, 2008 episode of Raw, Regal won an over-the-top battle royal to face Santino Marella for the Intercontinental Title, and the next week in Manchester, England, Regal defeated Marella in a 40 second squash match to win his second Intercontinental Title. Later, he entered into a feud for the title with number one contender CM Punk. On the January 5 edition of Raw, Regal lost to Punk via disqualification after he grabbed the referee's shirt. Due to this, Stephanie McMahon awarded Punk a rematch the following week, with the stipulation that if Regal was disqualified, Regal would lose the Intercontinental title, but this time Punk was disqualified. McMahon awarded Punk another rematch, this time a No Disqualification match on January 19 episode of Raw, Punk won the match and the title. Regal got a rematch but lost the match when Punk hit the Go To Sleep.
Following the Draft, Regal was left alone on the Raw brand as his on-screen manager Layla was drafted to the SmackDown brand. At Extreme Rules, Regal unsuccessfully challenged Kofi Kingston for the WWE United States Championship along with Montel Vontavious Porter and Matt Hardy, Kofi Kingston retained the United States Championship by pinning Regal.
After a couple of weeks absent from television, he returned to in-ring competition on the July 21, 2009 edition of ECW on SyFy, against new-comer Yoshi Tatsu.
Regal was named the number one contender for the ECW Championship on the August 11, 2009 edition of ECW on SyFy, defeating Tommy Dreamer later on in the main event. On the August 18, 2009 edition of ECW on SyFy, Regal teamed with Vladimir Kozlov against Christian and Ezekiel Jackson, with the end of the match involving Jackson turning on Christian, allowing Regal to pin Christian for the victory. The end result would have Regal becoming the leader of a new stable, The Ruthless Roundtable. At SummerSlam 2009, Regal challenged Christian for the ECW Championship, but was unsuccessful after losing to Christian in just 8 seconds. Regal then challenged Christian to a rematch for the title at WWE Breaking Point, but was once again unsuccessful. Regal received another shot for the ECW Championship on the November 10 edition of ECW on SyFy in Sheffield, England, but was once again unsuccessful.On the November 24 edition of ECW, William Regal lost to Yoshi Tatsu and blamed his associate, Ezekiel Jackson for it.Ezekiel Jackson then turned heel and choke bombed William Regal, along with Vladimir Kozlov. Regal later turned face and threw Kozlov into the announce table.