Cusack first became famous in the mid-1980s for appearing in teen movies such as Better Off Dead, The Sure Thing, One Crazy Summer, and Sixteen Candles. Cusack made a cameo in the 1988 music video for "Trip At The Brain" by Suicidal Tendencies. His biggest success in that genre is arguably his starring role as Lloyd Dobler in Cameron Crowe's Say Anything. He began broadening his choice of roles in the late 1980s and early 1990s with more serious-minded fare, such as the political satire True Colors and the film noir thriller The Grifters.

Cusack became a proven box office success with his roles in the black comedy Grosse Pointe Blank and the Jerry Bruckheimer blockbuster Con Air.He has since chosen a diverse range of roles, such as an obsessive puppeteer in Being John Malkovich, a lovelorn record store owner in High Fidelity, and a Jewish art dealer mentoring a young Adolf Hitler in Max. He starred in the horror film 1408, based on Stephen King's short story of the same name.