Wilmore grew up in suburban Los Angeles, the child of a Catholic family. His father is a doctor. He has a younger brother, Marc Wilmore, who is also a television writer, actor and producer.
Wilmore studied theatre at California State Polytechnic University, but dropped out to pursue acting and stand-up comedy.
Beginning in the 1980s, Wilmore appeared as an actor in several small film and television roles, including a recurring role as a police officer on The Facts of Life. In the early to mid-1990s, he worked on the writing staff of the talk show Into the Night With Rick Dees, the sketch comedy show In Living Color, and the sitcom Sister, Sister, where he also portrayed a bus driver in one episode. Wilmore went on to serve as a writer and producer on a series of sitcoms, including The Fresh Prince of Bel-Air and The Jamie Foxx Show.
In 1999, Wilmore co-created the animated comedy The PJs with Eddie Murphy and executive-produced the show until its conclusion in 2001. He subsequently co-created and produced The Bernie Mac Show (where he won an Emmy Award for writing the pilot episode) as well as creating and producing Whoopi (with Whoopi Goldberg). From 2005 to 2007, he was a consulting producer for The Office and made recurring appearances on the show playing Mr. Brown, a diversity consultant.
In 2006, Wilmore began appearing regularly on The Daily Show, where he is billed as the "Senior Black Correspondent" or a derivative form of the title, such as the "Senior Executive Commander-in-Chief Who Happens To Be Black Correspondent" following the election of Barack Obama. His work on the show frequently centers on humorous observations of the black experience in American society. In January 2009, Hyperion published Wilmore's I'd Rather We Got Casinos: And Other Black Thoughts, a political humor book described by Booklist as "a faux collection of articles, essays, radio transcripts, and letters exploring the more ludicrous angles on race." Wilmore originated the titular phrase in a January 2007 Daily Show appearance.
Wilmore has continued to make occasional acting appearances, including an uncredited role as a minister in the 2009 comedy I Love You, Man, and a supporting part in the 2010 comedy Dinner for Schmucks.