Micheaux was born near Metropolis, Illinois and grew up in Great Bend, Kansas, one of eleven children of former slaves. As a young boy he shined shoes and worked as a porter on the railway. As a young man, he very successfully homesteaded a farm in an all-white area of South Dakota where he began writing stories. Given the attitudes and restrictions on black people at the time, Micheaux overcame them by forming his own publishing company to sell his books door-to-door.

The advent of the motion picture industry intrigued him as a vehicle to tell his stories. He formed his own movie production company and in 1919 became the first African-American to make a film. He wrote, directed and produced the silent motion picture The Homesteader, starring the pioneering African American actress Evelyn Preer and based on his novel of the same name. He again used autobiographical elements in The Exile, his first feature film with sound, in which the central character leaves Chicago to buy and operate a ranch in South Dakota. In 1924 he introduced the moviegoing world to Paul Robeson in his film, Body and Soul.

Given the times, his accomplishments in publishing and film are extraordinary, including being the first African-American to produce a film to be shown in "white" movie theaters. In his motion pictures, he moved away from the "Negro" sterotypes being portrayed in film at the time. Additionally, in his film Within Our Gates, Micheaux attacked the racism depicted in D.W. Griffith's film, The Birth of a Nation.

The Producers Guild of America called him "The most prolific black - if not most prolific independent - filmmaker in American cinema." Over his illustrious career, Oscar Micheaux wrote, produced and directed forty-four feature-length films between 1919 and 1948 and wrote seven novels, one of which was a national bestseller.

Micheaux died in Charlotte, North Carolina while on a business trip. His body was returned to Great Bend, Kansas, where he was interred in the Great Bend cemetery with other members of his family.

In 1986 the Directors Guild of America honored Micheaux with a Golden Jubilee Special Award and today the Oscar Micheaux Award is presented each year by the Producers Guild.

For his contribution to the motion picture industry, Oscar Micheaux has a star on the Hollywood Walk of Fame at 6721 Hollywood Blvd.

There is a 1994 documentary about Micheaux, Midnight Ramble, named after the "Midnight Rambles" in which cinemas would show films at midnight to an African American audience.