Ruth Brown's father was a dockhand who directed the local church choir, but the young Ruth showed more of an interest in singing at USO shows and nightclubs. In 1945, Brown ran away from her home in Portsmouth along with a trumpeter, Jimmy Brown, whom she soon married, to sing in bars and clubs. She then spent a month with Lucky Millinder's orchestra, but was fired after she brought drinks to the band for free, and was left stranded in Washington, D.C.. Blanche Calloway, Cab Calloway's sister, arranged a gig for Brown at a Washington nightclub called Crystal Caverns and soon became her manager. Willis Conover, a local DJ, caught her act and recommended her to Atlantic Records bosses, Ahmet Ertegun and Herb Abramson. Brown was unable to audition as planned though, because of a serious car accident that resulted in a nine-month hospital visit. In 1948, however, Ertegun and Abramson drove to Washington from New York City to hear her sing in the club. Although her repertoire was mostly popular ballads, Ertegun convinced her to switch to urban blues.

At her first audition, in 1949, she sang "So Long", which ended up becoming a hit. This was followed by "Teardrops in my Eyes" (1950), "I'll Wait for You" (1951), "I Know" (1951), "5-10-15 Hours" (1953), "(Mama) He Treats Your Daughter Mean" (1953), "Oh What a Dream" (1954), "Mambo Baby" (1954) and "Don't Deceive Me" (1960). She also became known as Little Miss Rhythm during this period. In all, she was on the R&B charts for 149 weeks from 1949 and 1955, with 16 top 10 blues records including 5 number ones, and became Atlantic's most popular artist, earning Atlantic records the proper name of "The House that Ruth Built."

During the 1960s, Brown faded from public view to become a housewife and mother, and only returned to music in 1975 at the urging of Redd Foxx, followed by a series of comedic acting gigs, including a role in sitcom Hello, Larry and the John Waters film Hairspray, as well as earning a Tony Award for her Broadway performance of Black and Blue and a Grammy award for her album Blues on Broadway, featuring hits from the show. In 1993, she was inducted into the R&B Hall of Fame, as "The Queen Mother of the Blues".

Ruth Brown is a favorite artist and inspiration of a later blues artist, Miss Bonnie Raitt. Brown recorded and sang along with fellow rhythm and blues performer Charles Brown, a member of the Rock and Roll Hall of Fame, and toured with Miss Raitt on Raitt's tour in the late 1990s, "Road Tested".