As a young man, Walker met and learned from Blind Lemon Jefferson, another legendary blues musician. Walker's recording debut was "Wichita Falls Blues"/"Trinity River Blues", recorded for Columbia Records in 1929. His distinctive sound didn't develop until 1942, when Walker recorded "Mean Old World" for Capitol Records.
The bulk of Walker's output was recorded in the late 1940s with Black & White Records, starting with 1947's "Stormy Monday Blues", with its famous opening line, "They call it stormy Monday, but Tuesday's just as bad". He followed up with his "T-Bone Shuffle": "Let your hair down baby, let's have a natural ball". Both are considered blues classics. B. B. King says "Stormy Monday" first inspired him to take up the guitar.
Throughout his career he worked with top quality musicians, including Teddy Buckner (trumpet), Lloyd Glenn (piano), Billy Hadnott (bass), and Jack McVea tenor sax).
In addition to Black & White, he recorded for Imperial Records (backed by Dave Bartholomew), and Atlantic Records.
By the early 1960s, Walker's career had slowed down somewhat, in spite of a much-hyped appearance at the American Folk Blues Festival in 1962 with Memphis Slim, among others. A few critically acclaimed albums followed, such as I Want a Little Girl, and he won a Grammy in 1970 for Good Feelin' (Polydor). He died in 1975.