Wendie Jo had aimed for a performing-arts career from high school onward. She attended the summer Teenage Drama Workshop at California State University, Northridge, during the 1970s, and began her screen career at a young age when she was cast in the small role of "Kuchinsky," in Matthew Robbins' 1978 teen comedy Corvette Summer, alongside Mark Hamill. She appeared in Robert Zemeckis' period comedy I Wanna Hold Your Hand, as the irrepressible "Rosie Petrofsky." Sperber was overweight, but was able to move quickly on screen (Entertainment Weekly described Rosie Petrofsky as "a screaming Beatlemaniac who, among other things, climbed through elevator shafts and leapt from a moving car"), and her “girl-next-door” appearance helped her to overcome the stigma of her weight.
A scene in Back to the Future Part II involving her appearing as a hooker was canceled due to Wendie Jo being pregnant at the time. As she could not appear, it was also decided that an adjacent scene with brother Dave McFly as a drunk would not be included because fans would wonder what happened to her. She was brought back for Back to the Future Part III, where she appeared briefly at the end of the film.
Back to the Future was the fourth film in which comedienne Wendie Jo had worked with Robert Zemeckis and Bob Gale. She played the role of Beatles' fan Rosie Petrofsky in I Wanna Hold Your Hand (1978), Maxine Dexheimer in the film 1941 the following year, and "Nervous Nona" in Used Cars the year after that. She was then a regular on the TV series Bosom Buddies, with Tom Hanks and Peter Scolari, and in Hanks's film Bachelor Party, until being called back by Zemeckis and Gale for the role of Linda McFly.
Following her work on Part I, Sperber starred in the 1986 film Stewardess School, a typical 1980s misfit comedy. She plays a stewardess who saves a flight from a terrorist bombing, ironically when the wind pulls her to the bombed part of the plane and she is stuck there.
Sperber was diagnosed with breast cancer in 1997, and continued to work in television and film, as well as founding the cancer support center "weSPARK". After a remission, the cancer returned in 2002. She died at the age of 47 on November 29, 2005. Sperber's final television work was voicing a game show hostess on an episode of American Dad! which is produced by Seth MacFarlane, a BTTF fan who has sometimes included references to the films in his work. Sperber completed work on the American Dad! episode before her death and it was released posthumously in 2006. As a tribute to the late actress, MacFarlane gave her previously unnamed character the name "Wendie Jo".