The son of actor Richard Cusack and younger brother of comic actress Joan Cusack, John Cusack started his career at the age of eight, under the guidance of his theatrically active mother. He made his stage bow with Evanston's Pivan Theatre Workshop and quickly went on to do commercial work, becoming one of Chicago's busiest commercial voice-over artists.

Although Cusack began to emerge as an actor during the heyday of the Brat Pack, and appeared in a number of "teen" movies, he managed to avoid falling into the narrowly defined rut the phenomenon left in its wake. After making his film debut in 1983's Class, he had a brief but painfully memorable appearance as a member of Anthony Michael Hall's nerd posse in Sixteen Candles (1984). Bigger and better opportunities came Cusack's way the following year, when he achieved a measure of stardom with his portrayal of a sexually anxious college freshman in The Sure Thing (1985). The same year, he gained further recognition with his starring roles in Better Off Dead (which also granted him a degree of cult status) and The Journey of Natty Gann.

Cusack spent the rest of the 1980s carving out a niche for himself as both a solid performer and something of a lust object for unconventional girls everywhere, a status aided immeasurably by his portrayal of lovable underachiever Lloyd Dobler in Cameron Crowe's 1989 ....Say Anything. He also began winning critical acclaim for his parts in more serious films, notably as a disgraced White Sox third baseman in John Sayles' Eight Men Out (1988) and as a con artist in Stephen Frears' The Grifters (1990).

Cusack enjoyed steady work throughout the 1990s, with particularly notable roles in Woody Allen's Bullets Over Broadway (1994), which featured him as a struggling playwright; Midnight in the Garden of Good and Evil (1997), in which he starred as a journalist investigating a murder; Grosse Pointe Blank (1997), which cast him as the film's protagonist, a neurotic hit man; and the impressively cast The Thin Red Line, in which he played a World War II soldier. Just about all of Cusack's roles allowed him to showcase his quirky versatility, and the films he did to close out the century were no exception: in 1999 he first starred as an air-traffic controller in the comedy Pushing Tin and then appeared as Nelson Rockefeller in Cradle Will Rock, Tim Robbins' exploration of art and politics in 1930s America; finally, in perhaps his most unique film to date, he starred in Spike Jonze's Being John Malkovich as a puppeteer who discovers a way to enter the mind of the famous actor. The wildly original film turned out to be one of the year's biggest surprise hits, scoring among both audiences and critics. Cusack had yet another triumph the following year with High Fidelity, Stephen Frears' adaptation of Nick Hornby's novel of the same name. The actor, who co-wrote the script for the film in addition to starring in it, earned some of the best reviews of his career for his heartfelt comic portrayal of Rob, the film's well-meaning but oftentimes emotionally immature protagonist.

The next year he played opposite Julia Roberts in the showbiz comedy America's Sweethearts. In 2002 he took a lead part in the controversial Hitler biopic Max, and he did a brief cameo for Spike Jonze in Adaptation.

The next year he had a couple of hits with the John Grisham adaptation The Runaway Jury, and the psychological thriller Identity. In 2005 he was the lead in the black comedy The Ice Harvest opposite Billy Bob Thornton, as well as the romantic comedy Must Love Dogs.

He earned solid reviews in 2007 for the Iraq War drama Grace Is Gone, playing the husband of a woman who dies while serving in the military., and in that same year he starred in the Stephen King adaptation 1408. In 2008 he appeared in and co-wrote the political satire War, Inc. The next year he was the lead in the disaster film blockbuster 2012.

Cashing in on his status as an eighties icon, he had a hit in 2010 with the R rated comedy Hot Tub Time Machine, and in 2012 he portrayed Edgar Allan Poe in The Raven.