He also made a small guest appearance on an episode of David Wain's internet series, Wainy Days. In 2008, Mintz-Plasse next appeared with Paul Rudd and Seann William Scott in David Wain's film Role Models as Augie Farques, a nerdy teenager obsessed with medieval live-action role-playing games.

Upon release, the film earned critical and commercial success, with many critics citing Mintz-Plasse's performance as a highlight he received a nomination for the MTV Movie Award for Best Breakthrough Performance. Because he was 17 at the time and still a minor, his mother was required by law to be on set while he filmed his sex scene in the movie. When auditioning for the part of Fogell in his film debut Superbad, he had no professional head shots and instead took one with his camera phone. He is Jewish on his mother's side, whereas his father is from a Catholic family.

He is the son of Ellen Mintz, a school counselor, and Ray Plasse, a postal worker. Mintz-Plasse was born in Woodland Hills, Los Angeles, where he attended El Camino Real High School, performing on its improv comedy team.

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