Grable was set on the road to stardom by her mother, who enrolled her from an early age in dance and music classes and in 1929 moved with her to Hollywood. Only 13 years old, Grable lied about her age and landed chorus girl parts in several Hollywood musicals. She sang and danced in films throughout the 1930s (sometimes using the name Frances Dean) but did not make much of an impression until 1939, when she was a hit on Broadway in Cole Porter (Porter, Cole)'s musical Du Barry Was a Lady. She was then called back to Hollywood by Twentieth Century Fox, and in 1940 she had her first blockbuster success with Down Argentine Way. That film was followed by such hits as Moon over Miami (1941), Sweet Rosie O'Grady (1943), Pin Up Girl (1944), and The Dolly Sisters (1946)—the success of which helped pull Fox out of debt.

Grable ranked among the top 10 box office stars for 10 consecutive years (1942–51); she held the number one spot in 1943 and was the highest-ranked woman in 7 other years. At the height of her fame, her famous legs were insured for one million dollars, and she became not only the highest-paid star in Hollywood but the highest-paid woman in the United States. In the mid-1950s, however, Grable's movie career declined in tandem with the decrease in the popularity of the conventional, backstage musicals she specialized in. She then headlined shows in Las Vegas, Nevada, sometimes appearing with bandleader Harry James (James, Harry), to whom she was married from 1943 to 1965. (Her first husband, from 1937 to 1940, was actor Jackie Coogan (Coogan, Jackie).) She also starred in the road companies of hit stage shows and was one of the most popular repacement stars of the long-running Broadway musical Hello Dolly!