Melvin Udall, a cranky, bigoted, obsessive-compulsive writer of romantic fiction, is rude to everyone he meets, including his gay neighbor, Simon. After Simon is hospitalized, Melvin finds his life turned upside down when he has to look after Simon's dog. In addition, Carol, the only waitress at the local diner who will tolerate him, must leave work to care for her sick son, making it impossible for Melvin to eat breakfast.

In order to foil a terrorist plot, an FBI agent undergoes facial transplant surgery and assumes the identity of a criminal mastermind. The plan turns sour when the criminal wakes up prematurely and seeks revenge.