In 1975, she made her film debut with a small role in Hester Street, followed by small roles in several movies and television shows. In 1978, she appeared in the Jack Nicholson-directed Western Goin' South in 1978. She has since appeared in a large number of character roles. Many were for her brother, Robert Shaye, co-founder and former co-CEO of New Line Cinema, such as her role as Mrs. Flynn in the 1990 film Book of Love, which Robert Shaye directed. Her breakout comedy role was the part of Mrs. Nuegeboren in the Farrelly Brothers' Dumb and Dumber (1994). Shaye also appeared in the Farrelly's 1996 comedy Kingpin, and then got a role as Cameron Diaz's overtanned neighbor Magda in their 1998 hit There's Something About Mary. She followed this with 1999's Detroit Rock City as an uptight mother waging a personal war against the band Kiss.
Shaye has also appeared in four films by director Walter Hill: The Long Riders (1980), Brewster's Millions (1985), Extreme Prejudice (1987) and Last Man Standing (1996). In 2003, she appeared alongside Ray Wise and Alexandra Holden in the cult horror film Dead End as Laura Harrington, and as Jenny Buono, the mother of 1970s Los Angeles serial killer Angelo Buono in The Hillside Strangler. Most recently, she was seen in the thriller Snakes on a Plane. She also appeared in the film 2001 Maniacs as the part of Granny Boone.
In 2007, she appeared in the short films Sponsored By, Under The Gun, Midnight Snack, Time Upon a Once, Old Home Boyz, Backseat Driving Test, and The Yes Men which were directed by contestants on the reality show On the Lot.