Segel ha actuado en varias películas, incluyendo "Knocked Up" (2007), "Forgetting Sarah Marshall" (2008), "I Love You, Man" (2009), "Despicable Me" (2010), "Jeff, Who Lives at Home" (2011), "The Muppets" (2011), "The Five-Year Engagement" (2012), "Sex Tape" (2014) y "The Discovery" (2017).