Real-life rapper Lil Jon appeared in one 'A Moment in the Life of Lil Jon' sketch opposite Chappelle's exaggerated impression of him, speaking in an excessively dignified accent, and later credited the sketch with boosting his visibility.

Both Rick James and Prince confirmed that the wild stories told about them in the 'Charlie Murphy's True Hollywood Stories' sketches were true, with James's admission captured in unreleased interview footage and Prince telling MTV 'the whupping is true.'

Prince later used an image of Chappelle dressed as him from the sketch as the cover art for his single 'Breakfast Can Wait'.

In 2005, a real city council candidate in Hattiesburg, Mississippi, who happened to share the name Rick James, had his campaign signs defaced with 'bitch' added or stolen by fans referencing the show's catchphrase.

Charlie Sheen said he was hospitalized in 2010 after developing a hernia from laughing so hard while watching the 'Blind Supremacy' Frontline sketch.

According to Neal Brennan, the production team never used prerecorded/canned laughter for any sketch except the 'Dude's Night Out' segment, due to a lack of audience reaction during filming.

Wayne Brady reportedly had trouble filming his sketch because he found it difficult to deliver the line 'Is Wayne Brady gonna have to choke a bitch?'.

During a June 2004 stand-up show in Sacramento, Chappelle walked off stage after audience members kept shouting the 'I'm Rick James, bitch!' catchphrase, later returning to say the show was 'ruining his life' and that its popularity was hurting his stand-up career.

Chappelle told Oprah Winfrey that Comedy Central's official explanation for a production delay—that he had the flu—was untrue, and that stress had actually caused him to step away.

In April 2005 Chappelle flew to South Africa and stayed at what was reported to be a psychiatric facility, though a Time reporter who interviewed him there said no psychiatric treatment was occurring, and Chappelle later described the trip as a 'spiritual retreat.'

Chappelle said he felt the 'pixie sketch,' filmed in blackface as a minstrel-show character, was 'socially irresponsible' after noticing a white crew member laughing in a way that made him feel laughed at rather than laughed with.

Chappelle's decision to leave the show meant walking away from a $50 million contract with Comedy Central.

The Season 1 DVD became the best-selling TV series DVD set of all time as of 2005, surpassing sets from The Simpsons, American Dad!, Family Guy, Friends, and Seinfeld, and had sold over two million copies by 2010.

In late 2020 the series was pulled from Netflix and HBO Max less than two months after being added, following Chappelle's on-air comments about not receiving royalties from the show; it returned in February 2021 after he renegotiated his deal, though Season 3's 'Lost Episodes' were left off the platforms.