Cusack began acting in childhood. He attended the Piven Theatre Workshop in Chicago and he did many voice-overs for commercials and appeared in some stage productions by the age of 12. His first film was the comedy Class in 1983. Later, he was given the role of John Bender in John Hughes' film The Breakfast Club but was replaced by Judd Nelson. In 1988, he founded a theatre group ("The New Criminals"), for which he has directed several productions.

After success at an early age as the star of several teen-oriented films, Cusack has generally sought roles which cast him as an ethically conflicted everyman. He is often cast as an anti-hero who can be very neurotic, but has played a wide variety of characters. He frequently appears in films with members of his family (particularly his older sister, Joan) and with long-time best friend Jeremy Piven, whose parents, Byrne and Joyce Piven, founded and continue to run the Piven Theatre Workshop.

After playing mostly character roles for a number of years, Cusack became an A-list star in 1997 with the widely acclaimed black comedy Grosse Pointe Blank (which he also co-wrote and produced) and the action movie Con Air, both of which were very commercially successful. He continues to choose roles in movies outside the mainstream, however, such as Being John Malkovich and High Fidelity, which is largely considered to be a definitive role for the actor, as a troubled record store owner with too many relationship hangups. Among some of the films he has turned down include Indecent Proposal, Crash and Apollo 13.

Cusack spent a year at New York University before dropping out, reasoning that he had "too much fire in belly."

Since May 2005 he's been a contributing blogger at The Huffington Post.

He is not married, but has been romantically linked to a number of women. Cusack is fiercely protective of his private life and rarely makes public appearances between his films or events. He has said that "celebrity is the worst thing that can happen to an actor."