Her first major screen role was in 1980 in the films The Hollywood Knights and Falling in Love Again. However, both films failed to get her widespead notice. She tried a TV career when she starred in Great Yellow Bird, Fantasy Island, Callie & Son, Splendor in the Grass, "Scarface", and The Children Nobody Wanted. She returned to film in Grease 2; it was weakly received by critics and audiences, despite gaining a cult following.

It was not until 1983, when Pfeiffer co-starred with Al Pacino in Brian De Palma's gangster classic Scarface, that she caught the attention of Hollywood. In 1985, she starred in the fantasy romance Ladyhawke, which gave Pfeiffer good reviews, but failed to become a box office success. In 1987, she starred in The Witches of Eastwick, which was a box office smash and a critical success. Through 1988 and 1989, Pfeiffer earned worldwide critical acclaim in Married to the Mob, Dangerous Liaisons, and The Fabulous Baker Boys; those films also earned her