Born Antoinette Lees in Butte, Montana, she began her film career in 1934 playing bit parts and using her given name. As Andrea Leeds she played her first substantial role in the film Come and Get It (1936) and achieved another success with her next film It Could Happen to You (1937).
As part of an ensemble cast that included Katharine Hepburn, Ginger Rogers and Lucille Ball, Leeds was nominated for an Academy Award for Best Supporting Actress for her performance as an aspiring actress in Stage Door (1937). She read for the role of Melanie in Gone with the Wind, however the role was given to Olivia de Havilland.
Her wholesome quality led to her being cast in The Goldwyn Follies (1938) playing "Miss Humanity" - a woman considered by a jaded Hollywood executive to represent the ideal American woman. The film was not a success and received poor reviews.
She next appeared in two films opposite Joel McCrea, Youth Takes a Fling (1938) and They Shall Have Music (1939), for the first time playing the lead female role. She continued to play the romantic female lead in an adventure film set in the 1906 Philippines, The Real Glory, opposite Gary Cooper and David Niven, and opposite Don Ameche in the first Technicolor biography of Stephen Foster, Swanee River (1939).
Her final film, Earthbound (1940), was a fantasy murder mystery in which Leeds' character solves the murder of her husband, aided by his ghost.
These films were relatively successful and Leeds remained a popular actress. In 1939 she married Robert Stewart Howard, son of California businessman and racehorse owner Charles S. Howard, and decided to leave films to devote herself to raising a family. Her father-in-law owned and raced Seabiscuit, and with her husband she became a successful horse owner/breeder.
The Howards also owned the Howard Manor in Palm Springs, a hotel originally built as the "Colonial House" by Las Vegas casino owner and Purple Gang member Al Wertheimer. (The hotel is now operated as the Colony Palms Hotel, and features the "Winner's Circle Suite" in honor of Seabuscuit and the Howards.) After his death in 1962, Leeds ran a jewellery business. It was her only marriage, and produced two children, Robert Jr. and Leann, who died in 1971.
Andrea Leeds died from cancer in Palm Springs, California, aged 69. A resident of the city for many years, a Golden Palm Star on the Palm Springs Walk of Stars was dedicated to her in 1994.
She was interred in Desert Memorial Park in Cathedral City, California.