He is best known as a writer and actor for the American television show, Chappelle's Show. He is noted for having a ridiculously deep bag of "pimperish, prisony" catch phrases. Dave Chappelle once praised Murphy, saying he was "just as funny or funnier than a comedian."

Murphy's most famous contribution to the show is the "Charlie Murphy's True Hollywood Stories" sketches (spoofing the eponymous E! Entertainment Television show). In these, Murphy recounts his misadventures as part of his brother's entourage, including his encounters with various celebrities; most importantly the late Rick James and Prince. Murphy was associated with the late 80's hiphop group, K*9 Posse. The K*9 Posse was Vernon Lynch, Jr (Eddie and Charlie's half brother) and Wardell Mahone. Charlie Murphy is credited as the Executive Producer of the K*9 Posse's self-titled album as well as having writing credit on two tracks on the record, "Say Who Say What" and "Somebody's Brother." The latter track is written about Murphy himself reflecting on a relationship with a woman who was caught up in the excitement of being around all the famous people that Murphy associated with. But Murphy comes out on top with the lyrics, "You see I don't mind workin undercover, It's a blessing not a curse to be somebody's brother."

He also played club owner Gusto in the film CB4, appeared in the 1999 movie The Player's Club, and lent his voice to a character in the video game, Grand Theft Auto: San Andreas as a pimp named Jizzy-B.