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Leigh appeared in radio programs before her first formal foray into acting, making her film debut in the drama The Romance of Rosy Ridge (1947). With MGM, she appeared in many films which spanned a wide variety of genres, which include the crime-drama Act of Violence (1948), the drama Little Women (1949), the comedy Angels in the Outfield (1951), the romance Scaramouche (1952) and the western drama The Naked Spur (1953). She played dramatic roles during the late 1950s, in such films as Safari (1956) and Orson Welles's film noir Touch of Evil (1958). With RKO Radio pictures she co-starred in the romantic comedy Holiday Affair (1949) with Robert Mitchum.

Leigh achieved her biggest success starring as Marion Crane in Alfred Hitchcock's psychological thriller Psycho (1960). For her performance, Leigh won the Golden Globe Award for Best Supporting Actress and earned a nomination for the Academy Award for Best Supporting Actress. Intermittently, she continued to appear in films, including Bye Bye Birdie (1963), Harper (1966), Night of the Lepus (1972), and Boardwalk (1979). She made her Broadway debut in 1975 in a production of Murder Among Friends. She would also go on to appear in two horror films with her daughter, Jamie Lee Curtis: The Fog (1980) and Halloween H20: 20 Years Later (1998).

In addition to her work as an actress, Leigh also wrote four books between 1984 and 2002, two of which were novels. Leigh had two brief marriages as a teenager (one of which was annulled) before marrying actor Tony Curtis in 1951. The pair's highly publicized union ended in divorce in 1962, and after starring in The Manchurian Candidate that same year, Leigh remarried and scaled back her career. She died in October 2004 at age 77, following a year-long battle with vasculitis, an inflammation of the blood vessels.