- Dwayne "The Rock" Johnson as Derek Thompson, a hockey player who must work as a tooth fairy to earn back his lost tooth.
- Ashley Judd as Carly Robinson, Derek's girlfriend who is a dental hygienist.
- Julie Andrews as Lily, a tooth fairy who mentors Derek and teaches him about the magical world of tooth fairies.
- Stephen Merchant as Tracy, Derek's agent.
- Seth MacFarlane as Dr. Langley, a dentist and Carly's boss.
- Billy Crystal as Jerry, Derek's rival hockey player.
- Ryan Sheckler as Mick, a young hockey player who idolizes Derek.
- Destiny Whitlock as Tess, Carly's daughter who believes in the Tooth Fairy.
- Chase Ellison as Randy, Derek's young neighbor who steals his hockey stick.
- Brandon T. Jackson as Duke, a tooth fairy who becomes Derek's friend.