Born in Brooklyn, New York to Carl and Joyce Lewis, who are of African-American and Guyanese descent, Lewis began singing at the age of 4 and acting at 11. She graduated from the High School of Music and Art (now known as Fiorello H. LaGuardia High School) at age 16. After high school, she studied at the University of Miami, graduating cum laude with a major in Musical Theatre and a minor in Journalism in 1982.
She co-wrote the theme song to A Different World, with Bill Cosby and Stu Gardner, and co-performed the song for the first season. In A Different World, Lewis appeared for the first five of the six-season run as Jaleesa Vinson (later Vinson-Taylor) from 1987 to 1992. Although her character was married to another of the main characters on the show, her character disappeared from A Different World without explanation, like Chuck Cunningham of Happy Days.
Lewis appeared in a special week-long segment of A Different World called the Hillman College Reunion airing on Nick at Nite, along with Lisa Bonet, Jasmine Guy, Kadeem Hardison, Darryl M. Bell, Cree Summer, and Sinbad. On her Super Password appearance in 1988, she was paired with Dallas (1978 TV series) star Ken Kercheval, not any of her co-stars.
In Hangin' with Mr. Cooper, Lewis appeared in the first of the five seasons as Robin Dumars. She did not appear on the two shows concurrently — she left A Different World to star in Hangin' with Mr. Cooper. She and Holly Robinson Peete, along with R&B quartet En Vogue, performed the theme song for Season 1 of Mr. Cooper.
Lewis portrayed Deloris Van Cartier in Peter Schneider's Sister Act the Musical, which opened at the Pasadena Playhouse on October 24, 2006.
She has voiced Storm of the X-Men in three games, most recently Marvel: Ultimate Alliance 2. She also voiced Granny Grim on The Grim Adventures of Billy and Mandy, and voiced the female Shokan (Sheeva) in Mortal Kombat: Defenders of the Realm. Lewis has also done voice work as LaBarbara in Futurama, Detective Terri Lee on Spider-Man:The Animated Series and voiced a number of characters on The Boondocks.
She co-starred as Marigold Ballord in the Disney Channel Original Movie The Poof Point and also as Gail DeBarge in the Disney Channel Original Movie Let It Shine. In 2000, Lewis played Blabberwort the Troll in the miniseries The 10th Kingdom.
In 2006, Lewis starred as Melba Early in the film adaptation of Dreamgirls. Lewis released her debut CD, entitled Worth Waiting For, in 2006. She most recently played Addaperle in The Wiz with New York City Center's Encores!
In 2009, she played Denise Fields on One Tree Hill. In 2010, Lewis played a minor recurriung role as Lauren's mother in The Secret Life of the American Teenager. In 2012, she voiced Malora in Strange Frame. She also appeared as Dr. Knapp on Days of Our Lives in 2012–2013.
As of 2015, Lewis is playing a recurring role on Major Crimes as Patrice, a love interest for Lt. Provenza, whom he met during a case.
In March 2016, Lewis joined the vocal cast of Disney Junior's hit animated series Doc McStuffins as the voice of Grandma McStuffins.
Lewis was married to former NBA player Johnny Newman from 2004 until 2006.