She debuted in the silent film Cameo Kirby in 1923, and made a few silent movies, although it was her high-pitched, nasal voice which eventually made her a star in the talkies. In 1935 she starred opposite Edward G. Robinson in the gangster farce The Whole Town's Talking, and her popularity began to rise. It was her role opposite Gary Cooper in 1936 in Mr. Deeds Goes to Town that made her a star. She continued her fame by starring in Mr. Smith Goes to Washington in 1939, and again in 1943 in The More the Merrier, for which she was nominated for the Academy Award for Best Actress. She was even a contender for the role of Scarlett O'Hara in Gone With the Wind.
Her career began to falter in the late 1940s, and eventually, she retired from the screen, her last role being in the Western classic Shane in 1953.
After retiring, she taught drama at Vassar College.
She has a star on the Hollywood Walk of Fame at 6331 Hollywood Blvd.