Henderson was born in Buffalo, New York, and moved to New York City and became a popular song writer in Tin Pan Alley. For much of the late 1920s he worked in a partnership with Buddy De Sylva and Lew Brown.
His biggest hit songs included "That Old Gang of Mine", "Annabelle" (both 1923), "Bye, Bye Blackbird", "Five Foot Two, Eyes of Blue", "I'm Sitting on Top of the World" (all 1925), "Varsity Drag" ('26), "You're The Cream in my Coffee" ('28), "Button Up Your Overcoat", "You Are My Lucky Star" "I'm A Dreamer, Aren't We All", "Keep Your Sunny Side Up" ('29), "The Thrill Is Gone", and "Life Is Just a Bowl of Cherries" (1931).
Henderson also worked as an accompanyist to song and dance acts on Vaudeville and wrote music for the Zigfeld Follies and the George White Scandals.
Ray Henderson died in Greenwich, Connecticut.