He performed as a comedian and actor throughout the 1980s, including a year long stint on the sketch comedy series Saturday Night Live. His true breakthrough, however, came as writer and performer on FOX's sketch comedy show In Living Color (1990-1992), on his animated series Waynehead (1996-1997), and on his TV series Damon (1998).

Since then, he has starred in a number of films and television shows, some of which he has co-produced or co-written, including Beverly Hills Cop, The Last Boy Scout, and Major Payne and the sitcom My Wife and Kids. From 2016 to 2019, he starred as Roger Murtaugh in the television series Lethal Weapon. He is a member of the Wayans family of entertainers.