Santiago-Hudson first appeared as an actor in the 1988 film, Coming to America. He then played Captain Billy Cooper on the daytime drama Another World from 1990 to 1993, for which he became widely recognized. Santiago-Hudson made his Broadway debut as Buddy Bolden in Jelly’s Last Jam in 1992, and starred in August Wilson's Seven Guitars in 1995. He wrote 2001’s Lackawanna Blues, an autobiographical play, and then adapted it for the highly acclaimed, award-winning 2005 HBO film. He co-starred opposite Phylicia Rashad in Gem of the Ocean on Broadway in 2004. In 2007, he starred in a Public Broadcasting Service Nova documentary about the life of Percy Lavon Julian, and from 2009 to 2011, he played Captain Roy Montgomery in ABC's Castle. Santiago-Hudson returned to Broadway to star in Stick Fly in 2011, and directed August Wilson’s Jitney on Broadway in 2017.

Santiago-Hudson’s other feature film credits include Bleeding Hearts, Blown Away, Domestic Disturbance, Which Way Home, The Devil’s Advocate, American Gangster, Mr. Brooks, Shaft, Their Eyes Were Watching God, and Showtime’s Solomon and Sheba. His other television show credits include The Cosby Mysteries, New York Undercover, NYPD Blue, Touched by an Angel, The West Wing, Third Watch, Law & Order: Special Victims Unit, Showtime’s Billions, the TNT series Public Morals, and five episodes of Law & Order. He has also lectured on theatre at colleges and universities across the United States, and served as a private acting coach.

Santiago-Hudson received the 1996 Tony Award for Best Featured Performer in Seven Guitars. He was awarded the 2006 Humanitas Prize in writing for the HBO film adaptation of his play Lackawanna Blues, and received a NAACP Lifetime Achievement Theatre Award in 2009. In 2013, Santiago-Hudson won the Lucille Lortel Award for Outstanding Director, an Obie Award for Direction, and was nominated for the Drama Desk Award for Outstanding Director of a Play for his work in the Off-Broadway production of The Piano Lesson. In 2016, he won an Obie Award for Special Citations: Collaboration of the play Skeleton Crew. He has also received an honorary doctorate of letters from Buffalo State College in 2006, and from Wayne State University in 2015. In 2014, The Ruben Santiago-Hudson Fine Arts Learning Center was named in his honor in his hometown of Lackawanna, New York.

In 2017 he received a Tony Award nomination for Best Direction of a Play for "Jitney".

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