Williams began her acting career in 1989, appearing in episodes of The Cosby Show and Law & Order. In 1992, she was cast as Rhonda Blair, first and only black regular character, in the Fox prime time soap opera, Melrose Place. She was written off after only one season for lack of direction. “I think they didn’t make the effort to equip themselves [to write for a black character], either by hiring a black writer or asking me things,” – said Williams later. She later had guest starring roles on NYPD Blue and Living Single, before was cast as series regular in the ABC legal drama, Murder One (1995–1996) created by Steven Bochco. She received her first nomination an NAACP Image Award for Outstanding Supporting Actress in a Drama Series for her performance on show. In 1996, Williams had a recurring role as Dr. Grace Carr in the CBS medical drama series, Chicago Hope, for which she received NAACP Image Award for Outstanding Actress in a Drama Series nomination.

In film, Williams is best known for playing Keisha in the 1991 crime thriller New Jack City opposite Wesley Snipes and Ice T. She is also known for playing Anne-Marie McCoy in the 1992 horror Candyman opposite Tony Todd and Virginia Madsen. The following years she had small parts in Drop Squad (1994), Mother (1996), Punks (2000), Like Mike (2002), and Imagine That (2009) alongside Soul Food co-star Nicole Ari Parker. Williams has also starred in a number of made for television movies, including Emmy Award-nominated performance in Our America (2002). She also had roles in several smaller productions in recent years. In 2021, she will return to her role of Anne-Marie McCoy fourth films in the Candyman film series.

Williams married Andre Wiseman in November 1992 when the couple eloped. The couple have two sons together: Omar Tafari (March 5, 1997) and Haile Zion Ali (born 2003). In April 2018, Williams filed for divorce from Wiseman for the second time.

In 2000, Williams was cast as Maxine Chadway in the Showtime drama series Soul Food, a continuation of his successful 1997 film of the same name. Two other lead played by Nicole Ari Parker and Malinda Williams. In the 1997 film Vanessa L. Williams played the leading role of Teri Joseph, and Vivica A. Fox played Maxine. For her performance, Williams won NAACP Image Award for Outstanding Actress in a Drama Series in 2003, and received three additional nominations. The series aired to 2004 and went to be the longest running drama with a predominantly black cast in the history of American prime-time television.

After Soul Food, Williams had guest starring roles on Cold Case, Knight Rider and Lincoln Heights. In 2015, she was cast in a recurring role of Iris West’s mother in The CW drama series, The Flash. In October 2016, it was announced she was cast in the role of Valerie Grant on the NBC soap opera, Days of Our Lives.