Cotton began his professional career playing the blues harp in Howlin' Wolf's band in the early 1950s.

[4] In 1965, he formed the Jimmy Cotton Blues Quartet, with Otis Spann on piano, to record between gigs with the Muddy Waters band.

His first full album, on Verve Records, was produced by the guitarist Mike Bloomfield and the singer and songwriter Nick Gravenites, who later were members of the band Electric Flag.

[3] Williamson left the South to live with his estranged wife in Milwaukee, Wisconsin, leaving his band in Cotton's hands.

In 1965 he formed the Jimmy Cotton Blues Quartet, with Otis Spann on piano, to record between gigs with Waters's band.

[8] The James Cotton Blues Band received a Grammy nomination in 1984 for Live from Chicago: Mr. Superharp Himself!, on Alligator, and a second for his 1987 album Take Me Back, on Blind Pig Records.

On August 30, 2010, Cotton was the special guest on Larry Monroe's farewell broadcast of Blue Monday, which he hosted on radio station KUT in Austin, Texas, for nearly 30 years.

[11] Cotton's studio album Giant, released by Alligator Records in late September 2010, was nominated for a Grammy Award.

It includes guest appearances by Gregg Allman, Joe Bonamassa, Ruthie Foster, Delbert McClinton, Warren Haynes, Keb Mo, Chuck Leavell and Colin Linden.

[12] Cotton played harmonica on "Matches Don't Burn Memories" on the debut album by the Dr. Izzy Band, Blind & Blues Bound, released in June 2013.