Wayans was born in Harlem in New York City, the son of Elvira Alethia (Green), a homemaker, singer and social worker, and Howell Stouten Wayans, a supermarket manager. He has five sisters, Elvira, Vonnie, Nadia, Kim, Diedre, and four brothers, actors Marlon Wayans, Keenen Ivory Wayans, Shawn Wayans, and Dwayne Wayans. He was club footed as a child. This attribute would also be given to his character in My Wife and Kids and his character on the short-lived cartoon series Waynehead. Wayans attended Murry Bergtraum High School.
Damon started doing stand-up comedy in 1982. His earliest film appearance was a brief cameo as an effeminate hotel employee in the 1984 Eddie Murphy film Beverly Hills Cop. From 1985 to 1986, he appeared 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 on a live sketch, going against the script. In the Saturday Night Live 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 comedian.
With his brother Keenen, Wayans created the Fox sketch comedy series In Living Color, which had a mostly African-American cast. The show went on the air in 1990. It continued running until 1994, although Wayans left the show in 1992 to pursue a film career.
After In Living Color, he starred in films such as Mo' Money, The Last Boy Scout, Major Payne, Celtic Pride, Bulletproof, and The Great White Hype, and wrote and starred in the film Blankman. He also appeared in Janet Jackson's video "The Best Things in Life Are Free" and was considered for the role of The Riddler in Batman Forever (the role went to Jim Carrey, his co-star from In Living Color and Earth Girls Are Easy).
In 1996, he produced Waynehead, a short-lived cartoon for the WB, loosely based on his own childhood growing up in a large family, starring a poor boy with a club foot. The show only lasted a season due to poor ratings. From 1997 to 1998, he was the executive producer of 413 Hope St., a short-lived drama on the FOX network starring Richard Roundtree and Jesse L. Martin.
In 1998, he starred in the short-lived comedy TV series Damon, in which he played a Chicago detective. It aired on Fox. In 1999, his New York Times bestselling book Bootleg with co-author David Asbery was published; it is a humorous compilation of his observations about family.
Wayans starred in the ABC comedy series My Wife and Kids from 2001 to 2005.
In 2006, he produced and starred in the Showtime sketch comedy series The Underground, which also featured his son, Damon Jr. He also hosted the 2006 BET Awards.
In 2011, he also added author of a serious fictional novel to his credits with "Red Hats" which is the story of a suicidal 65-year-old woman who finds friendship and happiness when she joins the Red Hat Society.
As of 2014, Wayans continues to perform stand up comedy and has developed apps with his company of freelancers "MIMS" (Money in My Sleep). The company created applications such as Flick Dat, Diddeo and VHedz.
On November 12, 2015, at the Irvine Improv, Damon Wayans announced his retirement from stand-up commencing December 2015.
In 2016, he was cast as Roger Murtaugh in the television version of Lethal Weapon , a role originated by Danny Glover in the film series.
Wayans received four Emmy awards nominations for his acting and directing in In Living Color.
For his role in My Wife and Kids, he won the 2002 People's Choice Awards for Favorite Male Performer in a New TV Series, and received four International Press Academy "Golden Satellite Award" nominations.
Wayans was married to Lisa Thorner; they divorced in 2000. He has four children with Thorner: sons Damon Wayans Jr., Michael Wayans and daughters Cara Mia Wayans, Kyla Wayans; and is a grandfather. He is the uncle of Damien Dante Wayans, Chaunté Wayans and Craig Wayans.
Wayans is a close personal friend of both NBA legend Michael Jordan and fellow In Living Color star Jim Carrey.
Wayans was diagnosed with Type 2 diabetes in early 2013.
In September 2015, Wayans defended American comedian Bill Cosby from his sexual assault accusations, stating, "It's a money hustle". He continued, saying, "Forty years – listen, how big is his penis that it gives you amnesia for 40 years? If you listen to them talk, they go, 'Well, the first time…' The first time? Bitch, how many times did it happen? Just listen to what they're saying and some of them really is unrape-able. I look at them and go, 'You don't want that. Get outta here.'"Whiz (Homeboy Shopping Network)Homey D. ClownBlaine Edwards (Men on...)Mr.HHandi-ManReverend Ed CashAnton JacksonHead DetectiveTom Brothers (w/Keenen Ivory Wayans)Oswald BatesMaj. Benson PayneBabyface (on Saturday Night Live)Don King (on In Living Color)Little Richard (on Saturday Night Live and In Living Color)Louis Farrakhan (on both Saturday Night Live and In Living Color)Redd Foxx (on In Living Color)Richard Pryor (on In Living Color)Fab Morvan (on In Living Color)Jamie Foxx (on In Living Color)