Broderick began his career as a computer hacker who almost starts WW III in War Games. In Ferris Bueller, he was a success, and with his performances in two Neil Simon hits, Brighton Beach Memoirs (which earned him his first Tony) and Biloxi Blues. In 1987, an unexpected tragedy occurred while taking a drive in the Irish countryside with his then-girlfriend, Jennifer Grey. He crossed into oncoming traffic and crashed into another car, killing its two occupants, a mother and daughter. His injuries were severe enough to keep him hospitalized for two months. Broderick went on trial for "careless driving" and was fined $175.

More roles came in films such as Glory, opposite Denzel Washington and Morgan Freeman, and The Freshman, opposite Marlon Brando and a Komodo dragon. He earned another Tony as the star of the Broadway revival of How To Succeed in Business Without Really Trying. In 1996, Broderick played straightman to twenty-million-dollar-man Jim Carrey's obsessive freak in The Cable Guy, and then made a directorial debut with Infinity, a bittersweet love story based on the memoirs of Nobel Prize-winning physicist Richard Feynman.

His most recent movie, Broderick joined Meg Ryan to essay revenge, jilted-lover-style, in Griffin Dunne's 1997 feature-directorial debut film Addicted to Love. Broderick married his long-time love, Sarah Jessica Parker in 1997.