Patrice O'Neal began his comedy career in his native Boston at an open mic at Estelle's Bar and Grill in October 1992. In the late 1990s, he moved to New York City, where he became a regular at the Comedy Cellar, before relocating to Los Angeles, in the hopes of finding greater fame. Limited to guest roles in television and small TV roles, O'Neal has publicly discussed the frustrations and how they took their toll on him: "I'm telling you, if I'd have had a gun back then, I would have shot myself."
Frustrated by his lack of success in Los Angeles, Patrice O'Neal relocated to the United Kingdom to work on his comedy there. He worked harder as an outsider and a foreigner to gain the respect of his peers, and after some months he became a fixture in the UK clubs. He returned to the New York area in 2002 when he got the offer to do his first half-hour special for Showtime. The following year, he recorded a Comedy Central Presents special. It was also at this time he became a fixture on Tough Crowd with Colin Quinn on the same network.
Patrice O'Neal had many guest appearances on television. His first television appearance was on The Apollo Comedy Hour where he performed his Malcolm XXL bit. From there, he moved on to appearances on Showtime at the Apollo, FNight Videos, and a brief stint as a writer for the WWE. He appeared in guest-starring roles on MTV’s Apt 2F, Assy McGee, Ed, Z Rock, Yes Dear, Arrested Development, Chappelle Show and The Office. O'Neal was a regular on the Fox series The Jury, and he starred in the Comedy Central animated program Shorties Watching Shorties, along with Nick DiPaolo. He supplied the voice of Harold Jenkins on Noggin’s animated program O'Grady High and was featured as Jesus in Denis Leary’s Searchlight. In 2005, O'Neal filmed a half-hour One Night Stand special for HBO, and shortly thereafter became the first host of VH1's Web Junk 20. O'Neal left the show after two seasons, expressing concerns that the show's audience was too different from his own. In 2006 and 2007 he joined Opie and Anthony's Traveling Virus Comedy Tour, playing large outdoor concert arenas across the country.
Since his move back to New York in 2002, Patrice O'Neal became a recognized radio personality as a regular guest and occasional co-host on the Opie and Anthony program. Along with Bill Burr and Robert Kelly, he filled in as co-host for comedian Jim Norton while he filmed Lucky Louie. From 2006 to 2008, O'Neal hosted an call-in relationship advice show on XM Radio, which ended when the satellite network merged with rival Sirius. Initially promoted as Bitch Management, the show was titled The Black Philip Show, a reference to Dr. Phil. Dante Nero co-hosted, and a rotating cast of female comedians have played third mic. The show aired until the station suspended much of its Saturday night programming due to budget concerns. O'Neal had also appeared as a guest on other radio shows like Alex Jones and The Howard Stern Show and numerous guest appearances on political talk shows on the Fox News channel.
Living in the New York area, he performed at comedy clubs in the area, including headlining appearances at Comix comedy club and Caroline's. In February of 2011, Comedy Central aired his first hour-long special, Elephant in the Room. Patrice O'Neal started a web series and podcast called The Patrice Oneal Show - Coming Soon![4] showing various episodes as of May 15, 2007. He performed with a five-person group—Bryan Kennedy, Dante Nero, Vondecarlo Brown, Harris Stanton and Wil Sylvince—touching on many fictional scenarios. The show was produced by For Your Imagination and can be found on O'Neal's website. He guest-starred in another For Your Imagination-produced show, called Break a Leg, playing Adult-Sized Gary Coleman. O'Neal voiced Jeffron James in Grand Theft Auto IV, on an in-game radio show, Fizz!.
On September 19, 2011, Patrice was one of the many roasters at The Comedy Central Roast of Charlie Sheen. This would be his final television appearance before his death two months later.
On October 26, 2011, it was announced on The Opie and Anthony Show that Patrice O'Neal had suffered a stroke a week earlier, on October 19. He died from complications from his stroke a month later on November 28, 2011. Patrice O'Neal had struggled with diabetes and weight issues for several years.