Born Mary Frances Luecke in St. Louis, Missouri, her mother involved her with child modeling and at the age of eighteen, she was voted Missouri's "Junior Miss" and went on to win the 1961 national title of America's Junior Miss that earned her a university scholarship. She studied drama at Northwestern University in Evanston, Illinois then worked for a time as the host of a morning television show in Chicago. As an actress, she appeared in a few motion pictures, but worked primarily in television. Mary Frann made her screen acting debut in the television movie Nightmare in Chicago which was originally broadcast as an episode of Kraft Suspense Theatre in 1963.

From 1974 to 1979 Frann was a regular cast member of the afternoon soap opera, Days of Our Lives, and also made guest appearances on primetime dramas such as The Rockford Files. She is best remembered for her role as Joanna Loudon, the wife of Dick Loudon played by Bob Newhart in the popular situation comedy, Newhart that ran from 1982 to 1990. In the years after Newhart she worked mainly as a guest star in other series and television movies.

Outside of the entertainment business, Frann was active as a volunteer fundraiser and involved with charitable works. The night before her unexpected death, she had been working at the Los Angeles Mission, a Christian, non-profit organization dedicated to alleviating the suffering of hungry and homeless men and women on the city's Skid Row.

Frann died in her sleep of cardiac failure at her home in Beverly Hills, California and was interred in the Holy Cross Cemetery in Culver City, California.