In 1954, two U.S. marshals investigate the disappearance of a patient from a psychiatric hospital for the criminally insane on an island in a rural Massachusetts. They run into trouble when they are deceived by the hospital's crew chief administrator, a natural disaster hits and an inmate riot traps them on the shutter-looking island.
- Leonardo DiCaprio as Teddy Daniels, a U.S. marshal investigating the disappearance.
- Mark Ruffalo as Chuck Aule, a U.S. marshal and Teddy's partner.
- Ben Kingsley as the hospital's crew chief physician, Dr. John Cawley.
- Michelle Williams as Daniels' ex-wife.
- Emily Mortimer as the escaped patient Rachel Solando.
- Max von Sydow as Dr. Jeremiah Naering, one of the hospital's physicians.
- Jackie Earle Haley as George Noyce.
- Ted Levine as the Jail Warden of the Hospital.
- John Carroll Lynch as McPherson, a security guard at the Hospital.
- Elias Koteas as Andrew Laeddis.
- Patricia Clarkson as Ethel Barton.