Williams began portraying Jesse Hubbard on All My Children in 1981. His character became involved in a love affair with upper middle classAngie Baxter (Debbi Morgan). The characters eventually married and thus Darnell Williams was one half of the first African American supercouple on an American soap opera. Williams won two Daytime Emmy Awards for his work on All My Children in the 1980s. During the mid-1980s, both he and Morgan co-hosted a dance show titled "New York Hot Tracks," that also featured music videos.
Williams had a recurring role as the counsellor on the primetime drama Felicity, and worked as a director and acting coach for All My Children.
In May 2007, Williams joined the cast of Guiding Light in the recurring role of the villainous Griggs, a man who A.C. Mallet was once employed by as a hit-man. He appeared in the play Spalding Gray: Stories Left to Tell in New York City through June 2007. In 2008, Williams, along with Gregori J. Martin, co-directed the independent film Manhattanites, starring Ilene Kristen, Forbes March, and Aiden Turner, Williams's co-star.
Williams returned to All My Children in January 2008 as Jesse Hubbard, along with Debbi Morgan, who plays Dr. Angie Hubbard. He appeared on "Oprah- the Last Season" with cast mates Debbi Morgan and Michael E. Knight in 2011.
In September 2011, Darnell Williams concluded his run on All My Children along with the rest of the cast, due to the cancellation of the serial. At the time All My Children ended, Williams was the oldest contracted male actor cast member with the show and the second oldest contracted actor after Susan Lucci.
In January 2012, it was confirmed that Williams will be joining the cast of the CBS daytime drama The Young and the Restless, where he will reunite with All My Children co-star Debbi Morgan.
Williams returned in the new internet version of All My Children, reprising his role of Jesse Hubbard. The new show premiered on iTunes, Hulu and Hulu Plus on April 29, 2013.