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Mann nasceu em San Francisco, na Califórnia. Ela começou a fazer anúncios aos 17 anos de idade, vencendo a 500 outras actrizes num casting para o seu papel de The Cable Guy. Ela participou em filmes como George of the Jungle, Big Daddy, The 40 Year-Old Virgin e Knocked Up.
Mann é casada com o argumentista e realizador, Judd Apatow, de quem tem duas filhas, Iris e Maude. Conheceram-se nas filmagens de Cable Guy (1996), produzido por ele. O seu colega actor Jim Carrey, achou-a parecida com a Marlene Dietrich.
Foi nomeada nos Prémios 2007 da Chicago Film Critics Association Awards 2007 como melhor actriz secundária em Knocked Up.
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