He is best known for his roles as Ben Wyatt in the NBC sitcom Parks and Recreation (2010–2015) and Mark Scout in the Apple TV+ psychological thriller series Severance (2022–present).

[11] Scott has appeared in films including Hellraiser: Bloodline (1996), Star Trek: First Contact (1996), The Lesser Evil (1998), High Crimes (2002), The Aviator (2004), Torque (2004), Monster-in-Law (2005), The Matador (2005), Knocked Up (2007), Step Brothers (2008), The Vicious Kind (2009), Piranha 3D (2010),[12] Friends with Kids (2012), The Secret Life of Walter Mitty (2013), and Krampus (2015).

His other major studio comedies include Hot Tub Time Machine 2 and the Christmas comedy-horror film Krampus, both in 2015.

He starred as Caleb Sinclaire in the 2010 film The Vicious Kind, for which Scott was nominated for an Independent Spirit Award for Best Actor.

[19] Scott's early television roles include Griff Hawkins in Boy Meets World, Josh on Party of Five, a law intern on Murder One, as well as David's love interest, Ben Cooper, on Six Feet Under.

His first series regular role was on the controversial and sexually-explicit HBO drama Tell Me You Love Me (2007) as Palek, a husband struggling to conceive with his wife.

He appeared as a guest star in the second season before becoming a main character for the remainder of the series, which ended in 2015, during which time he received nominations for two Critics' Choice Television Awards.

Scott continued his streak of comedic roles in several episodes of Ken Marino's The Bachelor parody Burning Love and on David Wain's Wet Hot American Summer: Ten Years Later.

In 2020, Scott hosted the one-season ABC game show Don't, executive produced by Ryan Reynolds.

[31] Scott has had numerous guest appearances, including in the Adult Swim comedy Childrens Hospital and HBO's Veep.

[32] The series is introduced at the outset of each episode as "the comprehensive and encyclopedic compendium of all things U2," though it generally uses discussion of the band as a jumping off point for improv and absurdist humor.

In February 2018, Scott and Aukerman launched another podcast in the same format, this time covering the career and work of the band R.E.M., titled R U Talkin' R.E.M.