The son of a black father and a white mother, he had a tumultuous childhood in which the family moved frequently. They moved to St. Louis when Chester was 14 so his brother could be treated at Barnes Hospital for blindness he suffered as the result of a chemistry experiment gone awry.

Himes eventually moved to Cleveland, OH and attended Ohio State University, but was expelled for not studying. Himes took up gambling, pimping, passing false checks, stealing cars, and assault. He was arrested for robbery and spent seven years in the penitentiary. While there he developed his penchant for writing. After he was released he moved to Los Angeles and won a Rosenwald Fellowship in 1944, which led to his first published novel, If He Hollers Let Him Go. He married, moved to New York City, and wrote about life in Harlem.

After his divorce in 1953, he moved to Paris, where he became a writer of crime fiction. The film rights to his book, Cotton Comes to Harlem were sold to Samuel Goldwyn, who turned it into a movie. He then moved to Spain where he was recognized for his literary achievements by the Carnegie Endowment for International Peace.