Will Arnett made his film debut in the 1996 mystery thriller ‘Close Up’ where he played the role of ‘Dave.’ That same year, he also appeared in the American romantic comedy film ‘Ed's Next Move’ directed by John Walsh. He was next seen in films like ‘The Broken Giant’ (1997), ‘Southie’ (1999), ‘The Waiting Game’ (1999), ‘The Acting Class’ (2000), and ‘Series 7: The Contenders’ (2001). In 2003, he joined the cast of the American television sitcom ‘Arrested Development’ created by Mitchell Hurwitz. He portrayed George Oscar "G.O.B." Bluth II and remained a part of the series until 2006. He made a return to the show in 2018 and continued to appear on the show until 2019. Arnett also received the ‘TV Land Award’ for his performance in the series. He also appeared in the television series such as ‘Will & Grace’ (2004), ‘Odd Job Jack’ (2005), ‘Danny Phantom’ (2005), ‘Freak Show’ (2006), ‘O'Grady’ (2006), and ‘King of the Hill’ (2007). In 2007, he joined the cast of the American satirical sitcom television series ‘30 Rock’ created by Tina Fey. He portrayed Devon Banks in the series which earned him ‘Primetime Emmy Awards’ nominations. The series aired its final episode in 2013.
In 2008, he portrayed Lou Redwood in the American sports comedy film ‘Semi-Pro’ directed by Kent Alterman. The film was largely panned by critics and was a commercial failure. That same year, he also voiced ‘Vlad Vladikoff’ in the American computer-animated adventure comedy film ‘Horton Hears a Who!’ directed by Jimmy Hayward and Steve Martino. The film earned praise from critics and was a commercial success, grossing over $298.6 million on a budget of $85 million. He continued to star in films like ‘Spring Breakdown’ (2009), ‘Brief Interviews with Hideous Men’ (2009), ‘Jonah Hex’ (2010), ‘Despicable Me’ (2010), ‘Mansome’ (2012), ‘The Lego Movie’ (2014), ‘Teenage Mutant Ninja Turtles’ (2014), ‘Teenage Mutant Ninja Turtles: Out of the Shadows’ (2016), ‘The Lego Batman Movie’ (2017), ‘The Nut Job 2: Nutty by Nature’ (2017), ‘Teen Titans Go! To the Movies’ (2018), ‘The Lego Movie 2: The Second Part’ (2019), ‘Dolittle’ (2020), and ‘Rumble’ (2021). He was last seen in the American period romantic comedy television series ‘Our Flag Means Death’ in 2022.