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Mintz-Plasse nasceu em Los Angeles, Califórnia, filho de Ellen Mintz, uma conselheira escolar e Ray Plasse, um carteiro. Christopher é judeu e foi criado em West Hills, Califórnia. Frequentou a El Camino Real High School de 2003 a 2007, e recebeu aula particular no set de Superbad - É Hoje, antes de voltar para a escola para os dois meses concluintes. Ele é fã do Boston Celtics.
Mintz-Plasse não possuía nenhuma experiência atuando, exceto em montagens escolares, antes de aparecer em Superbad - É Hoje. Ele foi escolhido para o papel de "Fogell" (ou "McLovin") depois de uma audição entre colegas de escola. A lei obrigou sua mãe a estar presente no set de filmagens durante a sequência em que o personagem de Mintz-Plasse faz sexo com uma garota. O ator, à época, tinha apenas 17 anos.
Em 2008, ele apareceu no talk show, Jimmy Kimmel Live, cantando no coro durante o segmento "I'm Fucking Ben Affleck".
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