Because of his personal and professional association with Johnson, he became known as "Robert Junior" Lockwood, a nickname by which he was known among musicians for the rest of his life,[7] although he later frequently professed his dislike for this appellation.

[8] He often played with his quasi-stepfather Robert Johnson and with Sonny Boy Williamson II and Johnny Shines.

Lockwood played at fish fries, in juke joints, and on street corners throughout the Mississippi Delta in the 1930s.

[9] Around 1937–1938 Lockwood worked with Williamson and Elmore James in the Delta, at places like Winona, Greenwood, and Greenville (where they most probably met Johnson, who died in 1938).

[10] On July 1, 1941, Lockwood made his first recordings, with Doctor Clayton, for the Bluebird label in Aurora, Illinois.

In 1941, Lockwood and Williamson began their influential performances on the daily radio program King Biscuit Time on KFFA in Helena.

[13] For several years in the early 1940s the pair played together in and around Helena and continued to be associated with King Biscuit Time.

[15] In the early 1960s, as Bob Lockwood Jr. and Combo, he had a regular gig at Loving's Grill, at 8426 Hough Avenue.

From the 1970s through the 2000s, he performed regularly with his band the All Stars at numerous local venues, including Pirate's Cove, the Euclid Tavern, Peabody's, Flipside Tavern, Wilbert's, Brother's Lounge, and, in the last years of his career, Fat Fish Blue (on the corner of Prospect and Ontario in downtown Cleveland) every Wednesday night.

His most famous 12-string was a blue instrument custom designed and made by the Japanese luthiers Moony Omote and Age Sumi.

A live performance by Lockwood, Henry "Mule" Townsend, Joseph "Pinetop" Perkins, and David "Honeyboy" Edwards, recorded in 2004 and released in 2007 as Last of the Great Mississippi Delta Bluesmen: Live in Dallas, won a Grammy Award in 2008 in the Best Traditional Blues Album category.