His other notable film appearances include roles in Lincoln (2012), The Butler (2013), Selma (2014), If Beale Street Could Talk (2018), Ma Rainey's Black Bottom (2020), Zola (2021), and The Color Purple (2023).

Domingo was born and raised as the third of four children in Philadelphia, Pennsylvania by his mother, Edith Bowles, and her husband in a working class household.

[citation needed] Domingo continued to act sporadically through the 1990s, making his television debut in the police procedural Nash Bridges in 1997.

[20] On stage, Domingo starred as Mr. Franklin Jones, Joop, and Mr. Venus in the critically acclaimed rock musical Passing Strange,[21] which, after a successful 2007 run at The Public Theater, opened on Broadway on February 28, 2008.

[23] In 2010, Domingo's self-penned, one-man autobiographical play titled A Boy and His Soul premiered Off-Broadway at the Vineyard Theatre, for which he won a Lucille Lortel Award for Outstanding Solo Show.

[28] When The Scottsboro Boys opened in London, Domingo was nominated for the Laurence Olivier Award for Best Performance in a Supporting Role in a Musical in April 2014.

[30][31] Around this time, he also booked supporting roles as Private Harold Green in Steven Spielberg's historical epic Lincoln (2012), as Lawson Bowman in 42 (2013), as Freddie Fallows in The Butler (2013), and as Ralph Abernathy in Selma (2014).

[19][32][33] According to The New York Times, Domingo considered "quitting the acting business over the rejection" in 2014 after working as an actor for 30 years due to missing out on several television auditions, including one for a small role on Boardwalk Empire because casting directors allegedly said that his skin was too dark.

[34] Domingo described breaking down with emotions after being rejected for a role he and others felt was perfect for him and subsequently decided his talents weren't best used in acting, and he should instead pursue a business in photographing headshots.

"[19][35] On Fear the Walking Dead, Domingo portrayed the character of Victor Strand; his first appearance was in the fifth episode of the first season, titled "Cobalt".

In 2016, Domingo appeared in various television series, with roles such as Dr. Russell Daniels in The Knick,[19] Father Frankin Lucifer,[38] and Dr. Evers in Louis C.K.

[19]In 2017, Domingo joined the Academy of Motion Picture Arts and Sciences as a member of the Actors' Branch,[41] and played a dragonfly in an episode of the fourth season of the Netflix animated series BoJack Horseman.

[52] That year, he also received acclaim for his supporting role as Cutler in the Netflix adaptation of August Wilson's play Ma Rainey's Black Bottom, alongside Viola Davis and Chadwick Boseman.

Upon the announcement of his being cast in the lead role, the Bayard Rustin Center for Social Justice voiced their approval directly to Domingo, espousing that "Your powerful voice helps amplify Bayard Rustin, Godfather of Intersectionality, Planned the March, Brought non-violence to the Movement, Inspired the Freedom Riders, Lost to history because of who he loved, Who he was.

[68] It was also announced Domingo is set to direct and star in the leading role of an untitled Nat King Cole biopic from a script he co-wrote.

[69] In September 2024, it was reported that Domingo is slated to appear in Steven Spielberg's next film project, along side Emily Blunt, Josh O'Connor, Eve Hewson, and Colin Firth.