Patrice O'Neal was a regular guest on Tough Crowd with Colin Quinn. He was also featured in Contest Searchlight along with Denis Leary and Lenny Clarke. He has had half-hour specials on Showtime and Comedy Central Presents. He frequently performs at comedy clubs in New York, including Caroline's and the Comedy Cellar on occasion. O'Neal may appear to have a bold and loud style; he always voices his opinions. He has an outstanding delivery and has the ability to appear as if he is winging his set. He is one of the top comedians working in New York. In October 2005, he had a half-hour HBO stand-up special as part of the series One Night Stand.

O'Neal was also a booker and scriptwriter for the World Wrestling Federation on both of their major shows Monday Night RAW and SmackDown! from 2000-2002.

He currently co-stars in the Comedy Central animated stand-up comedy program Shorties Watching Shorties, with Nick DiPaolo. He also supplies the voice of Harold Jenkins on the animated program O'Grady. Additionally, he is a regular visitor to the Opie and Anthony program on XM Satellite Radio High Voltage channel 202. He is the "Third back-up third-mic" after Jimmy Norton and Bill Burr. Patrice plays Lonny on the US adaption of the TV Show The Office.