A native of Memphis, Tennessee, Nix came from a musical family (his brother, Larry Nix, became a mastering engineer for Stax and for the Ardent Recording Studios in Memphis). Don Nix began his career playing saxophone for the Mar-Keys, which also featured Steve Cropper, Duck Dunn and others. The hit instrumental single "Last Night" (composed by the band as a whole) was the first of many successful hits to Nix's credit. Without Nix, the Mar-Keys evolved into Booker T. & the M.G.'s.

As a producer, Nix worked with other artists and producers, such as Leon Russell of Shelter Records; Gary Lewis and the Playboys in Dick Clark's Caravan of Stars; George Harrison, of the Beatles; and John Mayall and the Bluesbreakers. One notable achievement was his collaboration with Harrison, Russell, and many others in the production of the "Concert for Bangladesh", Nix agreed that he organized backing chorus group for benefit concert at Madison Square Garden in 1971