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Leslie was born Joan Agnes Theresa Sadie Brodel in Detroit, Michigan, and raised Roman Catholic. She began performing as a singer at the age of nine as part of a vaudeville act with her two sisters; Betty and Mae Brodel. She later began her Hollywood acting career while still a child, performing under her real name in several movies, beginning with her debut in the MGM movie Camille (1936) with Greta Garbo and Robert Taylor.

The talented young actress soon signed a contract with Warner Bros. In 1941, Leslie got her first major role in the thriller High Sierra with Humphrey Bogart, playing a crippled girl under her new billing as "Joan Leslie". She also starred in Sergeant York and The Wagons Roll at Night in that same year. Later in 1942 she appeared as James Cagney's wife in Yankee Doodle Dandy, and at the age of 18 in 1943, she starred in The Sky's the Limit with Fred Astaire. In 1946 exhibitors voted her the most promising "star of tomorrow".

She starred in many more movies until 1950, when she married Dr. William Caldwell. Her last movie role was in The Revolt of Mamie Stover in 1956, and she eventually retired from acting altogether to look after her identical twin daughters Patrice and Ellen. She has appeared in several television commercials since then, and also made guest appearances in the TV shows Murder, She Wrote and Charlie's Angels. She also provided commentary as extras on the Yankee Doodle Dandy, Sergeant York, and High Sierra DVDs.

Joan was a regular volunteer at the Hollywood Canteen where she danced with the servicemen and granted hundreds of autographs. In 1944, she starred with Robert Hutton in the Warner Bros. film, Hollywood Canteen.

Joan Leslie has a star on the Hollywood Walk of Fame at 1560 Vine Street.