Lewis was born in Kinloch, Missouri, to a nurse's aide mother and a factory worker father. She attended Kinloch High School and then college at Webster University in Webster Groves, Missouri. Soon after she arrived in New York City, Lewis debuted on Broadway in a small role in Eubie (1979), the musical based on the work of Eubie Blake. She next landed the role of Effie White in the workshop of the Michael Bennett-directed musical Dreamgirls, but when the show moved to Broadway, Bennett chose Jennifer Holliday for the role.
Lewis accepted a position as a Harlette, a back-up singer for Bette Midler which led to Lewis' first TV appearances on Midler's HBO
specials. She also landed her first screen role as a result, appearing
as one of the buxom chorines in the 'Otto Titsling' production number in
the Midler vehicle Beaches (1988). At the same time, Lewis was developing her nightclub act, The Diva Is Dismissed, an autobiographical comedy and music show in New York City cabarets. She performed the show off-Broadway at the Public Theater.
In 1987, Lewis was hired as the Pre-Show announcer on the Star Tours ride at Disneyland. In 1988, Lewis relocated to Los Angeles. In 1992, she was cast as one of the back-up singers to Whoopi Goldberg in Sister Act. Goldberg sponsored several performances of The Diva Is Dismissed as a possible HBO series. In 1992 to 1993, she played Dean Davenport in the sixth and final season of A Different World. She also had a recurring role as Will Smith's Aunt Helen on The Fresh Prince of Bel-Air, as well as stints on a few episodes of In Living Color, reprising several of her characters from her nightclub act. Also in 1993, she played the mother of Tupac Shakur's character in Poetic Justice.
In 1993 she played the role of Tina Turner’s mother in the biopic
What's Love Got to Do with It (film). In 1994, she followed with other
supporting roles, including Mrs. Coleman the Unemployment Office lady in
Renaissance Man and as Whoopi Goldberg's sister in Corrina, Corrina. In 1995, she was cast in maternal roles to Kadeem Hardison in Panther and to Larenz Tate in Dead Presidents before she accepted the role of a lesbian judge on the short-lived CBS series Courthouse. Lewis returned to the big screen as Theresa Randle's telephone sex line boss in Spike Lee's Girl 6. She then played Whitney Houston's character's mother in Penny Marshall's The Preacher's Wife.
In 1999, she starred in the made-for-TV film Jackie's Back, a mockumentary about the struggling comeback of a diva in turmoil. She recently appeared in The Cookout, Nora's Hair Salon, Shark Tale and Cars. She was in a few episodes of Friends as Monica Gellar's co-worker. Since 2000, she has played Lana Hawkins on the Lifetime television medical drama Strong Medicine, the show ended February 2006. She also had a recurring role as Veretta Childs (Toni's mother) in the sitcom Girlfriends. In 2006, she had a featured role as the wedding planner in Tyler Perry's Madea's Family Reunion, and also appeared in the film Meet the Browns.
In one episode of That's So Raven she played the titular character's maternal grandmother, who has psychic powers. She recently starred as a judge in Boston Legal and appeared in the 2008 film Meet the Browns. On April 22, 2008, Lewis replaced Darlene Love as Motormouth Maybelle in Broadway's Hairspray, a role that was originally written for her.
In June 2010, Lewis' distinctive voice was in fine form as she told
The Jazz Joy and Roy syndicated radio show, "I just did a production of
'Hello Dolly' at the 5th Avenue Theatre
in Seattle and it had to be one of the greatest productions that I have
ever done, because I got to just do a character, Dolly Levi, and it was
In 2012 Lewis began working with Shangela
on the online reality show parody, "Jenifer Lewis and Shangela," where
she acts as herself alongside Shangela, a "drag queen living in her
basement." She later appeared in Shangela's music video for "Werqin Girl
Lewis has performed for many years on Broadway and has lent her
vocals to many of the television and film projects that she has been a
part of including the theme song for her most recognizable role, Strong Medicine.
Lewis' most recent singing role came with her role in the movie musical The Princess and the Frog.