McDowell was born in Rossville, Tennessee. His parents died when McDowell was young, and he moved often. By the age of 14, he was playing guitar.
He settled in Como, Mississippi in the 1920's, and worked steadily as a farmer, though he continued to perfom musically at various fuctions: dances, picnics and the like.
The 1950's brought a rising interest in blues music and folk music in the United States, and McDowell was brought to wider public attention, beginning when he was recorded in 1959 by Alan Lomax.
McDowell's recordings were popular, and he performed often at festivals and clubs. McDowell continued to perform delta blues much as he had for decades, but he sometimes perfomed on electric guitar rather than acoustic. While he famously declared "I do not play no rock and roll," McDowell was not averse to associating with many younger rock musicians: He coached Bonnie Raitt on slide guitar technique, and was reportedly flattered by The Rolling Stones straightforward, authentic version of his "You Got To Move" on their 1971 Sticky Fingers album.