Wayans was born in New York City, New York, the son of Elvira, a homemaker and social worker, and Howell Wayans, a supermarket manager. His family was involved in the Jehovah's Witnesses religion. He has four sisters, Vonnie, Nadia, Kim, Deidre, and four brothers, actors Marlon Wayans Keenan Ivory Wayans, Shawn Wayans, and Dwayne Wayans. He had a clubbed foot as a child. This attribute would also be given to his character in My Wife & Kids and his character on the cartoon series Waynehead. Wayans attended Murry Bergtraum High School.M/p>

His earliest film appearance was a brief cameo as an effeminate hotel employee in the 1984 Eddie Murphyfilm Beverly Hills Cop. He was briefly on Saturday Night Live as a featured performer, before getting fired for playing his character as a flamboyant gay cop instead of a straight cop. In the SNL book Live From New York, it was stated that Wayans did this largely due to growing frustrations that his sketches were not being considered for the show and increasing stress. He also appeared in the syndicated TV series Solid Gold during the 1980s as a stand-up comedian. After that, he went on to do the TV-show In Living Color from 1990 to 1992, part of a team that was nominated for Emmy Awards all three years.

In May of 2008 Wayans was highlighted by the media for the production of a controversial video titled, "Abortion Man". This viral video portrays a young man in need of killing the unborn child of his pregnant girlfriend and thus calls upon Abortion Man for aid. Abortion Man (portrayed as a super hero) then finds the pregnant girl and proceeds to knee, punch and stomp the girls stomach until the fetus flies out. Some sources hold that this video is satire and is an attempt to show the violence and cruelty of abortion while other sources think the video is simply a product of Wayans' distorted sense of humor.

Wayans was married to Lisa Thorner, however they divorced in 2000. He is the father of Damon Wayans, Jr., Michael Wayans, Cara Mia Wayans, and Kyla Wayans. He is also the uncle of Damien Dante Wayans and Craig Wayans. Wayans is a close friend of NBA legend Michael Jordan.