Totter began her acting career in radio in the late 1930s and after success in Chicago and New York, was signed to a seven year film contract with MGM Studios.

She made her film debut in Main Street After Dark (1945) and during the 1940s established herself as a popular female lead. Although she appearance in various film genres, she became most widely known to movie audiences in film noir productions. Initially MGM groomed her to become an important player and she was paired opposite some of their biggest stars. Among her successes were The Postman Always Rings Twice (1946) with John Garfield and Lana Turner, Lady in the Lake (1947) with Robert Montgomery and Jayne Meadows, The Unsuspected (1947 for Warner Brothers Studios) with Claude Rains, High Wall (1947) with Robert Taylor, The Saxon Charm (1948) with Montgomery and Susan Hayward, Alias Nick Beal (1949) with Ray Milland, The Set-Up (1949) with Robert Ryan, Any Number Can Play (1949) with Clark Gable and Alexis Smith, and Tension (1950) with Richard Basehart.

By the early 1950s the tough talking "dames" she was best known for portraying, were no longer fashionable, and as MGM began to work towards creating more family themed films, Totter was released from her contract. Totter for her part, was reported to have grown dissatisfied with MGM's handling of her career, only agreeing to appear in Any Number Can Play after Gable intervened.

She worked for Columbia Pictures and 20th Century Fox but the quality of her films dropped sharply and by the end of the decade her career was in decline. A continuing role in the television series Medical Center from 1972 until 1976 was the biggest success of her later years.

Totter's most recent TV appearance was in a 1987 episode of Murder, She Wrote.