After appearing in local productions and dancing in the chorus at Grauman's Chinese Theatre while still in high school, Loy entered films soon after she graduated. She appeared as an extra in several films before she was cast as a chorus girl in the landmark film The Jazz Singer (1927). She continued honing her craft in every role from ingenue to exotic vamp.

By the mid-1930s she was one of MGM's biggest stars and apopu-lar female box office attraction. Her first breakout hit was Manhattan Melodrama (1934), the film that John Dillinger was watching before he was gunned down outside a theater. That same year, after a long apprenticeship in silent films, she starred in the first of six Thin Man films, The Thin Man, opposite William Powell as the affluent and urbane couple Nick and Nora Charles, who solved murders amid witty repartee. They became the prototype for many later detective couples, including the Harts in the hit television series, Hart to Hart (1979-1984).

In 1937 the readers of Ed Sullivan's entertainment column voted Loy the “Queen of Hollywood". During the war, however, Loy turned her back on Hollywood and served as a full-time Red Cross worker. When the war ended she returned to films, and in addition to such classics as The Best Years of Our Lives (1946), she appeared as Lillian Gilbreth in another popular series of films based on the book Cheaper by the Dozen.

She was never awarded an Oscar for her acting, but in 1991 she received an honorary Oscar “in recognition of her extraordinary qualities both on screen and off, and with appreciation for a lifetime's worth of indelible performances". Unable to attend the ceremony because of failing health, via satellite from New York the actor simply said, “You've made me very happy. Thank you very much".

After her retirement from films, Loy became involved in politics and served as an advisor to the National Committee Against Discrimination in Housing as well as film advisor to UNESCO. She made her Broadway debut in the 1973 revival of The Women and appeared in several television productions. Her autobiography, Myrna Loy: Being and Becoming, was published in 1987.