On 8 June 2002, Lewis defended his title against Mike Tyson. Ticket sales were slow because they were priced as high as US $2,400, but a crowd of 15,327 turned up to see boxing's then biggest event at the Pyramid Arena in Memphis, Tennessee. Tyson also had to pay Lewis $335,000 out of his purse for biting him at the news conference announcing the fight, which was originally scheduled for 6 April 2002 in Las Vegas. Las Vegas, however, rejected the fight because of Tyson's licensing problems and several other states refused Tyson a licence before Memphis finally bid US $12 million to land it.
Lewis was forced to vacate the IBF title in 2002 after refusing to face mandatory challenger Chris Byrd. In May 2003, Lewis sued boxing promoter Don King for US $385 million, claiming that King used threats and bribery to have Tyson pull out of a rematch with Lewis and a fight on the card of a Lewis title defence.
In 2002, Lewis was reportedly offered £5m by World Wrestling Entertainment (WWE) chairman Vince McMahon to take up professional wrestling in his industry. His camp held discussions over a possible match with Brock Lesnar in February 2003, at the No Way Out pay-per-view event. Prior to the offer Lewis was familiar with wrestling; he was part of the famous match held in the old Wembley Stadium between The British Bulldog and Bret "The Hitman" Hart for the Intercontinental Championship at SummerSlam in 1992, representing the Bulldog during his entrance while bearing a Union Flag.
In 2002, Lewis played himself on an episode of The Jersey called "It's a Mad Mad Mad Mad Jersey".