Wayne Maurice Henderson was born September 24, 1939, in Houston, Texas, and began studying trombone in sixth grade. He co-founded the Jazz Crusaders in 1961 alongside pianist Joe Sample, tenor saxophonist Wilton Felder, and drummer Stix Hooper. His horn charts, worked out in tandem with Felder, became one of the signature elements of the band's evolving sound as it moved from hard bop into jazz-funk over the following fifteen years. The band's own story, including its 1971 rename to the Crusaders, is told in full in The Crusaders' JazzProfiles.com profile.

Henderson stepped back from the band's touring lineup in 1976 to focus on record production, forming his own company, At Home Productions. He produced Ronnie Laws's influential 1975 debut Pressure Sensitive alongside George Butler, and went on to produce records for Monk Montgomery, Gabor Szabo, Caldera, Pleasure, and his own former bandmate Wilton Felder, while working in various capacities with Ramsey Lewis, Patti Austin, and Marvin Gaye. His production and arranging credits span jazz, funk, and fusion records well beyond the Crusaders' own catalog.

He continued to release solo albums as a leader from the late 1960s through 2003, including Big Daddy's Place (1977) and 1980's Prime Time, a collaboration with vibraphonist Roy Ayers. He revived the Jazz Crusaders name with a new lineup in 1995 and later joined the faculty of the California College of Music in Pasadena in 2007.

Henderson died April 5, 2014, in Culver City, California, from heart failure after a long struggle with diabetes; he was 74.

Henderson's arranging and production work is arguably his most consequential contribution to crossover jazz: as a producer he helped shape the jazz-funk sound of artists like Ronnie Laws well beyond his own catalog as a trombonist, extending the Crusaders' aesthetic influence into an entire generation of adjacent records.