His father Richard Cusack was an actor, and his siblings Ann, Bill, Joan, and Susie have all been actors.
John began acting in childhood. He attended the Piven Theatre Workshop in Chicago and by the age of 12, John he had done voice-overs for commercials and appeared in some stage productions. His first film was the comedy Class in 1983. In 1988, John founded a theatre group ('The New Criminals') and has directed several productions.
Cusack is often cast as an anti-hero, but has played a wide variety of characters. He frequently appears in films with members of his family (particularly Joan) and with Jeremy Piven, whose parents ran the Piven Theatre Workshop.
He is not married.