In 1968, Hemphill moved to St. Louis, Missouri, and co-founded the Black Artists' Group (BAG), a multidisciplinary arts collective that brought him into contact with artists such as saxophonists Oliver Lake and Hamiet Bluiett, trumpeters Baikida Carroll and Floyd LeFlore, and writer/director Malinke Robert Elliott.

Hemphill was probably best known as the founder of the World Saxophone Quartet, a group he formed in 1976, after collaborating with Anthony Braxton in several saxophone-only ensembles.

Late in his life, ill-health (including diabetes and heart surgery) forced Hemphill to stop playing saxophone, but he continued writing music until his death[7] in New York City.

In 2021, New World Records released a retrospective seven-disc box set album titled The Boyé Multi-National Crusade for Harmony featuring Hemphill in a variety of mostly live solo and group contexts.

[8] A source of information on Hemphill's life and music is a multi-hour oral history interview that he conducted for the Smithsonian Institution in March and April 1994, and which is held at the Archives Center of the National Museum of American History in Washington, D.C. Albums featuring Hemphill's music With World Saxophone Quartet