Mary Louise Weller was born in New York City and was raised in Los Angeles' Westwood area. The onetime top New York model made her film debut with an uncredited role in the 1973 Al Pacino cop drama Serpico. In 1978 Weller starred as a beautiful marine Biologist in the made-for-TV film Hunters of the Reef (1978), and then as professor Andrew Prine's college student lover in the haunted house horror film The Evil (1978). She achieved perhaps her greatest enduring cult movie popularity with her performance as prissy and uptight sorority sister Mandy Pepperidge in the 1978 hit comedy Animal House. After Animal House, Weller went on to appear in such films as The Bell Jar (1979), Once Upon a Spy (1980), Forced Vengeance (1982), Blood Tide (1982) and Q (1982).

She acted in several plays in New York and wrote the play Four Alone, which was performed at the Greenhouse Theater in Pasadena. Moreover, Mary Louise trained with the U.S. Equestrian Team as a teenager and has participated in horse-riding competitions. Weller tried to get a movie based on her own original script made about jockey Mary Bacon, but it never materialized. She's a first cousin to Writer Sheila Weller, who mentioned Mary Louise in her 2003 book Dancing at Ciro's. As of 2007, Weller is retired from acting.