Ruben Hudson was born in 1956 in Lackawanna, New York, the son of Alean Hudson and Ruben Santiago, a railroad worker. He later adopted his mother's maiden name as part of his compound surname. His father was Puerto Rican and his mother was African American. He went to Lackawanna High school, earned his bachelor's degree from Binghamton University, his master's degree from Wayne State University and received an honorary Doctor of Humane Letters from Buffalo State College and Wayne State University.
In 2003, he was the reader in Volume 13 of the HBO film, Unchained Memories: Readings from the Slave Narratives. The series was narrated by Whoopi Goldberg. He wrote Lackawanna Blues (2001), an autobiographical play in which he portrayed himself and some twenty different characters from his past, which was produced in New York at the Joseph Papp Theatre in 2001. He adapted it for a highly acclaimed, award-winning 2005 HBO film, in which the parts were played by different people. It won the Humanitas Prize and earned Emmy and Writers Guild of America Award nominations.
Santiago-Hudson appeared on Broadway in Jelly's Last Jam (1992), written by George C. Wolfe. He received the 1996 Tony Award for Best Featured Actor in a Play for his performance in August Wilson's Seven Guitars.

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