Townsend was born Henry Jesse James Townsend, in Shelby, Mississippi, and grew up in Cairo, Illinois. He left home at the age of nine because of an abusive father and hoboed his way to St. Louis, Missouri. He learned guitar while in his early teens from a locally renowned blues guitarist known as Dudlow Joe.
By the late 1920s he had begun touring and recording with the pianist Walter Davis and had acquired the nickname Mule, because he was sturdy in both physique and character. In St. Louis, he worked with some of the early blues pioneers, including J. D. Short.
Townsend was one of the only artists known to have recorded in nine consecutive decades. He first recorded in 1929 and remained active up to 2006. By the mid-1990s, Townsend and his one-time collaborator Yank Rachell were the only active blues artists whose careers had started in the 1920s. He recorded on several different labels, including Columbia Records, Bluesville Records, and Folkways Records.
Articulate and self-aware, with an excellent memory, Townsend gave many invaluable interviews to blues enthusiasts and scholars. Paul Oliver recorded him in 1960 and quoted him extensively in his 1967 work Conversations with the Blues. Thirty years later, Bill Greensmith edited thirty hours of taped interviews with Henry to produce a full autobiography, giving a vivid history of the blues scene in St Louis and East St Louis in its prime.
Townsend died on September 24, 2006, at the age of 96, at St. Mary's Ozaukee Hospital, in Mequon, Wisconsin, just hours after having been the first person to be presented with a "key" in Grafton's Paramount Plaza Walk of Fame.
While [Henry Townsend] did not scorn his old recordings, he had no taste for spending his later years simply recreating them.
Blues, for him, was a living medium, and he continued to express himself in it, most remarkably in his songwriting.
--Tony Russell, The Guardian
On February 10, 2008, Townsend was posthumously awarded a Grammy, his first, at the 50th Annual Grammy Awards. The award, in the category Best Traditional Blues Album, was given for his performances on Last of the Great Mississippi Delta Bluesmen: Live In Dallas, released by the Blue Shoe Project. Townsend's son, Alonzo Townsend, accepted the award on his behalf.