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Originally a stand-up comedian in Vancouver, Rogen moved to Los Angeles for a part in Judd Apatow's series Freaks and Geeks in 1999 and got a part in Apatow's sitcom Undeclared in 2001, which also hired him as a writer. Rogen landed a job as a staff writer on the final season of Da Ali G Show (2004), for which the writing team was nominated for a Primetime Emmy Award for Outstanding Writing for a Variety Series. Apatow subsequently guided him toward a film career.

His first movie appearance was a minor role in Donnie Darko (2001), and he had a supporting part in Apatow's directorial debut, The 40-Year-Old Virgin (2005), which he co-produced. He had leading roles in Apatow's comedies Knocked Up (2007) and Funny People (2009). Rogen and his writing partner, Evan Goldberg, co-wrote the films Superbad (2007), Pineapple Express (2008), The Green Hornet (2011), and This Is the End (2013) and directed This Is the End and The Interview (2014), all of which starred Rogen. He had further comedic roles in Zack and Miri Make a Porno (2008), Neighbors (2014), its 2016 sequel, The Disaster Artist (2017), and Long Shot (2019). He has played dramatic roles in 50/50 (2011), Take This Waltz (2011), Steve Jobs (2015) and The Fabelmans (2022). He also starred in the FX on Hulu miniseries Pam & Tommy (2022), for which he received Primetime Emmy and Golden Globe Award for Best Supporting Actor nominations.

Rogen co-developed the AMC television series Preacher (2016–2019), serving as writer, executive producer, and director. He has also executive produced the Amazon Prime Video superhero series The Boys from 2019 and Invincible from 2021. Rogen is also known for his voice roles in the animated films Shrek the Third (2007) and Horton Hears a Who! (2008), the Kung Fu Panda series, The Spiderwick Chronicles (2008), Monsters vs Aliens (2009), Sausage Party (2016; which he also co-wrote and produced), The Lion King (2019), The Super Mario Bros. Movie (2023), Teenage Mutant Ninja Turtles: Mutant Mayhem (2023; which he also co-wrote and produced) and Mufasa: The Lion King (2024).