Coca took lessons in piano, dance, and voice as a child and while still a teenager moved from Philadelphia to New York City to become a dancer. She got her first job in the chorus of the Broadway musical When You Smile, and became a headliner in Manhattan nightclubs with music arranged by her first husband, Robert Burton. She gained prominence when she began to combine music with comedy; her first critical success was in New Faces of 1934.
In the early days of live television, she played opposite Sid Caesar in a sketch comedy program, Your Show of Shows which was immensely popular from 1950 to 1954. She also had her own series, The Imogene Coca Show.
She was nominated for a Tony Award for her final Broadway performance as religious zealot Letitia Primrose in On the Twentieth Century, a stage musical adapted from the 1934 film Twentieth Century. Coca's role – a religious fanatic who plasters decals onto every available surface – was a male in the original film (played by actor Etienne Girardot; for the stage adaptation, the role was rewritten specifically as a vehicle for Coca.
In the 1963 TV season, Coca portrayed a comic temporary helper in the NBC sitcom "Grindl." It played opposite "The Ed Sullivan Show" and lasted a season.
Coca starred as a cave woman with Joe E. Ross in the 1966-67 TV time travel satire sitcom It's About Time. She made memorable guest appearances on the sitcoms Bewitched as "Mary the Tooth Fairy", The Brady Bunch as "Aunt Jenny", and on Mama's Family as Gert in the episode "Gert Rides Again". Her later years were spent in relative solitude with only occasional TV guest appearances on Moonlighting and in small movie roles, including her memorable role as "Aunt Edna" in National Lampoon's Vacation.