The daughter of a minister, Thornton was introduced to church music at an early age. A skilled singer and dancer and a self-taught drummer and harmonica player, she toured the American South as a member of Sammy Green's Hot Harlem Revue during the 1940s. Settling in Houston, Texas, in 1948, she came under the influence of blues greats Lightnin' Hopkins, Lowell Fulson, Junior Parker, and Clarence (“Gatemouth”) Brown. In the early 1950s she began performing with bandleader Johnny Otis (Otis, Johnny), with whom she recorded many songs for Peacock Records, including the Jerry Leiber and Mike Stoller (Leiber and Stoller) composition “Hound Dog,” a number one rhythm-and-blues (rhythm and blues) hit for Thornton in 1953 and an even bigger pop hit in 1956 for Presley, whose rock-and-roll (rock and roll) version owed much to Thornton's original.

As interest in blues declined, Thornton ceased recording but continued to perform in the San Francisco Bay area, where she came to the attention of Joplin, whose late 1960s version of the Thornton-written “Ball and Chain” revived interest in the blues singer called “Big Mama” because of her girth and larger-than-life voice and stage presence.