"Willie Mae just watched others and tried things."

One of seven children of a minister in Alabama, Thornton sang in church choirs along with her mother as a child. She was forced to begin working at age 14 when her mother died, and got her first chance to sing in public at a saloon where she scrubbed floors after the regular singer quit her job one night. After joining Sammy Green's Hot Harlem Review of Atlanta, Georgia, in 1941, she hit the road on the blues circuit throughout the South. While on tour she was treated to live performances by blues legends such as Bessie Smith, Memphis Minnie, and Big Maceo.

After settling in Houston in 1948, Thornton met Junior Parker, Lightning Hopkins, Lowell Fulson, and Gatemouth Brown, all of whom influenced her style. Her first recording was released in Houston under the name Harlem Stars. Next she signed a contract with the Peacock label and headed to Los Angeles to appear with bandleader Johnny Otis, who was well known on the pop music scene at the time. His tour included famous performers such as Little Esther and Mel Walker. With the Otis band on the Peacock label, Thornton recorded some 30 songs in the early 1950s that were "remarkable for the vocal presence and total cohesiveness," according to Gerard Herzhaft in the Encyclopedia of Blues.
Thornton's big break came in 1953 when, according to Bob Shannon and John Javna in Behind the Hits, Johnny Otis asked composers Jerry Lieber and Mike Stoller to write a song especially for Thornton. The song was "Hound Dog," and it climbed to number one on the R&B charts, making Thornton a national star. "They [Lieber and Stoller] were just a couple of kids then and they had this song written on a paper bag," Thornton told a columnist in New York City, claimed Stambler. "So I started to sing the words and join in some of my own. All that talkin' and hollerin'--that's my own."

Three years later, the song became a monster hit for Elvis Presley, with an arrangement similar to the original. Thornton always felt that she was cheated out of the success she deserved from "Hound Dog." The Penguin Encyclopedia of Popular Music noted that some people thought Thornton rather than Lieber and Stoller should have received credit for writing it. "I never got what I should have," she was quoted as saying by Stambler. "I got one check for $500 and I never seen another."

After "Hound Dog," Thornton kept busy at R&B showcases across the country. She traveled the circuit with friends Junior Parker and Johnny Ace in 1953 and 1954, then with Gatemouth Brown in 1956 before returning to California and taking up residence in Los Angeles the next year. As blues music declined in popularity in the late 1950s, Thornton was no longer in such demand, and she lost her recording contract in 1957. However, she continued to perform, playing drums and harmonica with small bands at local blues clubs in San Francisco. Thornton regained some of her lost limelight in 1961 with "Ball and Chain," which became a modest hit for her. Her star status continued to rise during the 1960s as white audiences began embracing blues music.

After appearing at the Monterey Jazz Festival in 1964, Thornton toured Europe as part of the American Folk Blues Festival. Her increasing popularity led to a new recording contract in 1965 with the Arhoolie label, an association that lasted into the 1980s. Her first Arhoolie album was recorded in Europe and featured a noteworthy lineup of James Cotton on harmonica, Otis Spann on piano, and Muddy Waters on guitar. Her visibility increased as she performed at Monterey again in 1966 and at various other jazz and blues festivals in the 1960s and 1970s. Her live appearances at two penitentiaries were also recorded In the 1970s.

Years of heavy drinking and hard-living had taken their toll on Thornton by the 1980s. But she continued to perform and remained popular in West Coast clubs up until the end of her life. "Emaciated, unable to remain standing, 'Big Mama' was still impressive with her swing during her last performances on stage," contended Herzhaft. She died of a heart attack in 1984 while living in a Los Angeles boarding house.