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