Described as "a stage-struck 17-year-old just out of high school", she started her career on the stage of the Muncie Civic Theatre. She quickly joined the Guild Theatre company, a new theatrical stock company in Cincinnati, Ohio. From that, she went to radio station WLW. Croft said of her work at WLW, "from 1935 to 1939, I played parts with every kind of voice and accent: children, babies, old women, society belles, main street floozies – everything."

Croft and Hal March co-starred in Too Many Cooks, a summer replacement program on CBS in 1950. The comedy centered on Douglas and Carrie Cook and their 10 children.

Croft married actor Jack Zoller, but the marriage did not last long, and the couple divorced. She remarried, to Elliot Lewis in 1959. She and Lewis remained wed until Lewis' death in 1990. Croft had a son, Eric, by her first marriage, who was killed in action during the Vietnam War.

In addition to her work with Lucille Ball, she was a frequent guest star on other television programs, including Howard Duff's adventure/drama series Dante in the 1960 episode "The Misfortune Cookie".

When Vance left The Lucy Show after the 1964-1965 season, Croft became Lucy's new sidekick, Mary Jane Lewis. Croft had previously had a recurring role as Audrey Simmons during the show's early seasons set in Danfield, New York. Mary Jane Lewis was Croft's legal name at the time, as she was then married to actor-producer Elliott Lewis (who had originally produced The Lucy Show during its first two seasons) but continued to use her maiden name professionally. Her only son, by a prior marriage, was killed in the Vietnam War during the period that she was co-starring with Ball.

The Lewis character was maintained when The Lucy Show was transformed into Ball's third sitcom, Here's Lucy. The character remained until Ball decided to end Here's Lucy in 1974.

Croft continued to act in television for several years after the end of Here's Lucy, even reuniting with Ball in 1977 in the special, Lucy Calls the President. She also returned to radio for several episodes of Sears Radio Theater in 1979.

She was a regular on at least two other series, as Clara Randolph the ebullient neighbor with the shrill voice married to Joe Randolph played by Hollywood veteran Lyle Talbot on The Adventures of Ozzie and Harriet and on Our Miss Brooks on CBS, in which she reprised her radio role as Miss Daisy Enright, the title character's rival. She provided the voice for Cleo the basset hound in Jackie Cooper's NBC series The People’s Choice (1955–58).