Barksdale played bass and banjo before settling on guitar, and moved to Chicago early in the 1930s. His first major engagement there was in Erskine Tate's band, which he followed with a stint behind Eddie South. Toward the end of the decade he began collaborating with Benny Carter. In the early part of the next decade, Barksdale moved to New York City, where he found work in studios and on radio for CBS.
Barksdale's credits as a session player in the 1940s and 1950s are extensive. He played with vocal ensembles such as The Blenders and The Clovers, and accompanied vocalists like Dean Barlow and Maxine Sullivan. Much of this work was due to his association with producer Joe Davis. He began working with Art Tatum late in the 1940s, taking Tiny Grimes's spot in his trio alongside bassist Slam Stewart. The association with Tatum would continue until 1956, when Barksdale became musical director of The Ink Spots. The following year, he played on Mickey & Sylvia's hit "Love Is Strange". He played for many years in the house band of ABC, and played on recordings by Lena Horne, Sammy Davis, Jr., Dinah Washington, and Sarah Vaughan. Among his other jazz associations are Milt Hinton, Buddy Tate, Clark Terry, and Louis Armstrong in his later years.
Barksdale retired from active performance in the 1970s and moved to California. He died there in 1986.
- Louis Armstrong: Louis Armstrong And The Angels/ Louis And The Good Book (Universal, 1957–58)
- Chet Baker: Verve Jazz Masters 32 (Verve, 1955–65), Baker's Holiday (Emarcy, 1965)
- Sidney Bechet: 1941-1944 (Classics)
- Billy Butler: Yesterday, Today & Tomorrow (Prestige, 1970)
- Benny Carter: 1940-1941 (Classics)
- Edmond Hall: 1944-1945 (Classics)
- Johnny Hodges: Jazz Masters 35 (Verve, 1951–67)
- Billie Holiday: The Complete Original Decca Recordings (GRP, 1944-1950)
- Jimmy Rushing And The Buck Clyton All-Stars: Jimmy Rushing and the Smith Girls (CBS/Fresh Sound, 1960)
- Maxine Sullivan: 1941-1946 (Classics)
- Art Tatum: The Complete Capitol Recordings of Art Tatum (Capitol, 1949-52)
- Clark Terry and Chico O'Farrill: Spanish Rice (Impulse!, 1966)
- Eddie South: 1923-1937 (Classics)