Lockwood played with Sonny Boy Williamson in the Clarksdale, Mississippi area in 1938 and 1939. He also played with Howlin' Wolf and others in Memphis, Tennessee around 1938. From 1939 to 1940 he split his time playing in St. Louis, Missouri, Chicago, Illinois and Helena.
In 1941, Lockwood made his first recordings with Doctor Clayton for the Bluebird label in Aurora, Illinois. During these same sessions, he also recorded the four songs which were released as the first two singles under his own name, which were early versions of his staple repertoire. These recordings were released as 78s on Bluebird Records.
Also in 1941, Lockwood and Williamson were featured on the first King Biscuit Time radio program on KFFA in Helena. For several years in the early 1940s the pair played together in and around Helena and continued to be associated with King Biscuit Time. From about 1944 to 1949 Lockwood played in West Memphis, Arkansas, St. Louis, Chicago and Memphis. Lockwood was an early influence of B. B. King and played with King's band during his early career in Memphis.
In 1950, Lockwood settled in Chicago. In 1954 he replaced Louis Myers as guitarist in Little Walter's band, and played on Walter's #1 hit "My Babe" in 1955. He left Little Walter's band shortly thereafter, and in the late '50s recorded several sessions with Sonny Boy Williamson for Chess Records, sessions which also included Willie Dixon and Otis Spann. Lockwood also performed and/or recorded with Sunnyland Slim, Eddie Boyd, and Muddy Waters among others.In 1961, Lockwood moved with his wife to her hometown of Cleveland, Ohio where he resided until his death. In the early 1960s, as "Bob Lockwood, Jr., and Combo," he had a regular gig at Loving's Grill, located at 8426 Hough Avenue. In the 1970s through the 1990s, he performed regularly with his band the "All Stars" at numerous local venues, including Pirate's Cove, The Euclid Tavern, and Peabody's. For the last few years of his career, Lockwood played at Cleveland's Fat Fish Blue (corner of Prospect and Ontario in downtown) every Wednesday night at 8 p.m.; the "All Stars" have continued to perform there after his death.
His Cleveland period also saw the release of some of his most noteworthy studio recordings as a band leader, first with a pair of albums playing solo and with his band of the time on the Trix Records label, and then with Johnny Shines for two LPs on the Rounder label. The latter showed both men determinedly playing the music they were interested in, rather than the familiar requests of the blues audience - an attitude Lockwood maintained. Although he seldom performed without his band, he also recorded a solo album of his own material, along with a few Robert Johnson standards, under the title Plays Robert and Robert. Lockwood has dealt briskly, sometimes brusquely, with the Johnson legend. It's typical that when he gave one of his infrequent album recitals of Johnson songs, for Plays Robert and Robert (1983), he puckishly chose to use a 12-string guitar.
In 2004, Lockwood appeared at Eric Clapton's first Crossroads Guitar Festival in Dallas, Texas. A live recording with three other blues musicians in Dallas in October 2004 – Last of the Great Mississippi Delta Bluesmen: Live In Dallas – was awarded a Grammy for Best Traditional Blues Album. or the late Henry Townsend and Robert Lockwood Jr. It was the first Grammy win for the musicians. His last known recording session was carried out at Ante Up Audio studios in Cleveland; where he performed on the album The Way Things Go, with long time collaborator Cleveland Fats for Honeybee Entertainment.
Lockwood died at the age of 91 in Cleveland, having earlier suffered a cerebral aneurysm and a stroke. He is buried at Riverside Cemetery in Cleveland