Cusack was born in New York City to Irish American Catholic parents Nancy and Richard Cusack, an actor and director; her brother is actor John Cusack. She grew up in Evanston, Illinois, where she studied drama at the Piven Theater Workshop. She attended the University of Wisconsin-Madison. She had her first major film role in 1980's My Bodyguard, at the age of 18.

Cusack was a cast member of Saturday Night Live for one season in 1985. Her other television work includes a short-lived series What About Joan (2001) and It's a Very Merry Muppet Christmas Movie (2002). She received Academy Award for Best Supporting Actress nominations for Working Girl (1988) and In & Out (1997).

To date, she and her brother John have appeared in eight movies together, including Say Anything (1989), Grosse Pointe Blank (1997) and High Fidelity (2000).

Cusack married Richard Burke in 1993, and they have two sons, Dylan and Miles. She has been the speaker for many of the US Cellular commercials.