Still was brought up by his mother and grandmother in Little Rock, Ark., and studied medicine at Wilberforce University, Ohio, before turning to music. He first studied composition at Oberlin Conservatory of Music in Oberlin, Ohio, then under the conservative George W. Chadwick at the New England Conservatory of Music, Boston, and later under Edgard Varèse during the latter's most radical avant-garde period. The diversity of Still's musical education was extended when, in the 1920s, he worked as an arranger for the dance-band leader Paul Whiteman and for the blues composer W.C. Handy (Handy, W.C.). In 1939 he married and settled in Los Angeles. Early orchestral works include Darker America (1924) and From the Black Belt (1926) for chamber orchestra.

Still's concern with the position of the blacks in U.S. society is reflected in many of his works, notably the Afro-American Symphony; the ballets Sahdji (1930), set in Africa and composed after extensive study of African music, and Lenox Avenue (1937); and the operas The Troubled Island (1938; produced 1949), with a libretto by Langston Hughes (Hughes, Langston), and Highway No. 1, U.S.A. (produced 1963 and 1977).

Still's compositions from the mid-1930s show the jazz band as a major influence on his eclectic musical style. He made considerable use of material in the African American style—though rarely borrowing actual melodies—and preferred simple, commercial harmonies and orchestration, the use of which, however, was characterized by the highest professionalism and seriousness of purpose.