Charlie Murphy first achieved widespread fame on Chappelle's Show, in the Charlie Murphy's True Hollywood Stories sketches. In these, Murphy recounts his misadventures as part of his brother's entourage, including his encounters with various celebrities including Rick James and Prince.

After Chappelle's Show host Dave Chappelle left the show, Murphy and Donnell Rawlings hosted the "lost episodes" compiled from sketches produced before Chappelle's departure.

He has done voiceovers for Budweiser radio commercials, Cartoon Network's Adult Swim series The Boondocks''Spongebob Squarepants and voiced a pimp named Jizzy-B in Rockstar Games' Grand Theft Auto: San Andreas video game. Recently, Murphy provided the voice for Spock on the G4TV's Star Trek 2.0 shorts.