Lewis is known unofficially as "The Mother of Black Hollywood" (also the name of her memoir) given her frequent matriarchal film and television roles.

[2][3] She also provided the voice for Mama Odie in Disney's animated feature The Princess and the Frog (2009), and Flo in Pixar's Cars series.

In 2014, Lewis began starring as Ruby Johnson in the ABC comedy series Black-ish, for which she received two Critics' Choice Television Award nominations.

Lewis was born in Kinloch, Missouri,[1] a suburb of St. Louis, to a nurse's aide mother, Dorothy, and a factory worker father.

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.

[6] After Lewis relocated to Los Angeles, she began appearing in television sitcoms, including Murphy Brown, Dream On, In Living Color, Roc, Hangin' with Mr. Cooper and Friends.

As a series regular, Lewis starred alongside Patricia Wettig in her short-lived legal drama Courthouse in 1995, playing Judge Rosetta Reide, the first main African American lesbian character on television.

[citation needed] In 1996, Lewis appeared as Theresa Randle's telephone sex line boss in the film Girl 6.

Later that year, she played Whitney Houston's character's mother in the film The Preacher's Wife,[8] for which she received her second NAACP Image Award nomination.

[9] In the same year, she began starring as Lana Hawkins on the Lifetime television medical drama Strong Medicine, for which she also performed the theme song.

[14] The following year, she starred alongside Rosario Dawson and Tracee Ellis Ross in Five, for which she received her third NAACP Image Award nomination.

[3] In 2014, Lewis was cast as Ruby Johnson, Anthony Anderson's character's mother in the ABC comedy series Black-ish.

[19] In 2024, Lewis competed in season eleven of The Masked Singer as "Miss Cleocatra" who later utilized an Egyptian throne prop.

[20] Also in 2024, the ABC special, After the Fall: A Conversation with Robin Roberts and Jenifer Lewis, premiered detailing a life threatening accident that happened while she was vacation in Africa.

[22][23] In 2015, Lewis was defrauded by a romance-scheme con man, which was detailed in the 2022 episode "Financial Infidelity", of the series American Greed.