She has appeared in numerous films, including The Cable Guy (1996), She's the One (1996), George of the Jungle (1997), Big Daddy (1999), Orange County (2002), The 40-Year-Old Virgin (2005), Knocked Up (2007), Drillbit Taylor (2008), I Love You Phillip Morris (2009), 17 Again (2009), Funny People (2009), This Is 40 (2012), The Other Woman (2014), and Blockers (2018).

In 1996, she appeared in The Cable Guy, followed with performances in Freaks & Geeks, Sam Weisman's George of The Jungle alongside Brendan Fraser, Big Daddy with Adam Sandler, Orange County opposite Jack Black, and The 40-Year-Old Virgin with Steve Carell.

[citation needed] In 2007, Mann starred alongside Seth Rogen, Katherine Heigl, and Paul Rudd in Judd Apatow's comedy Knocked Up, which grossed more than $218 million worldwide.

[10] Elle writer Mickey Rapkin said that "[Mann] owns the second half of 2009's Funny People, where her character does the most unlikely thing a woman can do in a major studio picture: has an affair with an ex-boyfriend on a whim.

"[11] That same year, Mann also starred in Burr Steers' successful comedy 17 Again opposite Zac Efron and Matthew Perry, which grossed over $125 million worldwide.

[14] She also lent her voice to "Linda", the main human character in Carlos Saldanha's animated film Rio, which earned over $484 million worldwide and also featured vocal performances by Jamie Foxx and Anne Hathaway;[15] as well as to Jonah Hill's animated FOX television series Allen Gregory, as the title character's second-grade teacher.

[citation needed] Mann continued her voice performance work in 2012 with her role in ParaNorman, an animated 3D stop-motion film from Chris Butler and Sam Fell.

[20] Mann and Apatow are both longtime supporters of the nonprofit organization 826LA, which focuses on encouraging and developing the writing skills of disadvantaged youth.