He founded the Collegians with Benny Carter and Rex Stewart while at Wilberforce College. He later changed the name to the Horace Henderson Orchestra, then the Dixie Stompers.
He was involved in the arrangement and composition of In the Mood, Christopher Columbus, and Big John Special, all of which became jazz standards.
His older brother was American pianist, bandleader, arranger, and composer Fletcher Henderson. He never surpassed Fletcher's fame.
He was pianist and musical director for Billie Holiday and Lena Horne.