Blackwell was born in LaGrange, Tennessee. He was introduced to the basics of the guitar by his father and neighbors, but, until the late 1930s, Blackwell performed on the piano in juke joints in Memphis. According to Blackwell's account however, after winning a competition against a rival musician, his adversary's friends beat Blackwell, crippling his hands. Undeterred and still hoping to pursue his music career, Blackwell requainted himself with the guitar, and allegedly received lessons from renown blues musician Robert Johnson. Travelling on Route 61, Blackwell became an iterinant musician, earning himself the nickname "61" for his regular use of the route as he performed up and down the Mississippi Valley and in New Orleans. In 1942, while on Beale Street in Memphis with fellow musician William Brown, Blackwell met Alan Lomax, a musicologist collecting field recordings of authentic country blues. Admittedly, Lomax was more interested in recording Brown than Blackwell who had taken to drinking moonshine, making it difficult for him to stay awake. From Lomax's own account in his book The Land Where the Blues Began, he took Blackwell and Brown to an Arkansas plantation in July 1942 to escape persecution from police for associating with the black musicians. Lomax recorded eight songs with Blackwell which were released on Bluebird Records and preserved by the Library of Congress. Following the session with Lomax, Blackwell never recorded again and kept a low profile, but his work was later rediscovered in the 1960s by blues historians Sam Stark and Ron Harwood, the latter of whom wrote about Blackwell in Jazz Journal, in 1967.
Blackwell died in 1972. In 1994, all of his songs were featured on the compilation album, Carl Martin / Willie "61" Blackwell - Complete Recorded Works in Chronlogical Order, released by Document Records.
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Blackwell spent much of his life in Memphis, where he still resided as late as the 70s. Among his early associates were Calvin Frazier (who was reputedly his nephew), stepson Robert Lockwood Jnr. and Robert Johnson. Another musician with whom Blackwell worked in Detroit was Baby Boy Warren. Blackwell was not a particularly inventive musician, but his circle paid keen attention to his original lyrics, and the eight songs he recorded for Bluebird in 1941 (together with two cut for the Library of Congress the following year) are the work of one of the most inventive lyricists in blues. No other singer reflects that hitching a ride would be easier if he knew Masonic hailing signs, or sees World War II as a chance to send his baby son ‘a Jap’s tooth’ to help ease the process of teething! Blackwell was a truly eccentric and unique artist.