He is widely known for his roles as Gob Bluth in the Fox/Netflix sitcom Arrested Development (2003–2006, 2013, 2018–2019) and the titular character in the Netflix animated series BoJack Horseman (2014–2020).

He has also starred, co-created, executive produced the Fox sitcom Running Wilde (2010–2011), and the Netflix comedy-drama series Flaked (2016–2017).

Arnett has acted in films such as Let's Go to Prison (2006), Blades of Glory (2007), Semi-Pro (2008), G-Force (2009), and Teenage Mutant Ninja Turtles (2014).

Known for his deep baritone voice, Arnett also took roles in Danny Phantom (2004–2007), Ice Age: The Meltdown (2006), Ratatouille (2007), Horton Hears a Who!

[12] As mentioned on the SmartLess podcast, Arnett is an avid hockey fan and workout enthusiast, known to often boast about his “Pro Dumper” and ability to bench press as much as 165 pounds.

[13] In 2001, Arnett was cast in the CBS television pilot, Loomis as the slacker brother of a local news reporter (Cheri Oteri), that was not picked up.

[14] In 2003, Arnett found mainstream success in television when he played George Oscar "Gob" Bluth II in the Fox comedy series Arrested Development and in 2006 he was nominated for his first Emmy.

[16] (He played Max the Magician in Sesame Street, in a nod to Gob Bluth's penchant for using Europe's "The Final Countdown" during his magic shows.

)[17] According to a 2006 interview with the Los Angeles Times, Arnett's two favourite episodes of the show were "Pier Pressure" and "Afternoon Delight".

[24] He guest-starred in King of the Hill and 30 Rock; in the latter, he played the recurring role of Devon Banks, Jack Donaghy's archnemesis, for which he was nominated for four Emmy Awards for Outstanding Guest Actor in a Comedy Series.

Arnett's distinctive gravelly voice has earned him voice-over work for CBS television promos, film trailers and numerous advertisements, including Lamisil medication.

[25] He has lent his voice to a number of television shows, such as Ghost Writer in the 2005 Nickelodeon's series Danny Phantom, Duncan Schiesst for the Comedy Central animated program Freak Show, which was created by and stars the voice of his Arrested Development co-star David Cross.

He has voiced characters in animated films, including Vlad in Horton Hears a Who!,[26] The Missing Link in Monsters vs. Aliens, Horst the German sous-chef in Ratatouille, and Mr. Perkins in Despicable Me.

In the Fox animated comedy series Sit Down, Shut Up, he voiced Ennis Hofftard, a bodybuilder who teaches English and always attempts to chase women.

[29] Arnett played supporting roles in the films Spring Breakdown, Hot Rod, The Comebacks, and On Broadway, where he once again worked with his close friend and director Dave McLaughlin.

[31] On November 17, 2009, it was announced that Arnett would try to win over real-life wife Amy Poehler in a guest spot on Parks and Recreation.

[33] In March 2012, Mansome, Arnett's first executive producer credit with Bateman, was announced as a Spotlight selection for the Tribeca Film Festival.

[34] The documentary, directed by Morgan Spurlock, is a comedic look at male identity as it is defined through men's grooming habits featuring celebrity and expert commentary.

[36] Arnett co-starred in the NBC television comedy series Up All Night, about a couple who struggle to balance their home lives (especially with their newborn child) and their work ones.

[citation needed] He voiced the eponymous character in the critically acclaimed Netflix animated sitcom BoJack Horseman, which ran from 2014 to 2020.

[43] He is the spokesman of a series of Hulu advertisements and his role in television spots deliberately recalls Devon Banks as a power-hungry manipulator.

[44] In 2021, Arnett played The Facts of Life's Dink Lockwood in a reenactment of the third season episode "Kids Can Be Cruel" for the third edition of Live in Front of a Studio Audience.

[47] Cursed Friends, a Comedy Central original movie from Arnett's production company Electric Avenue,[48] was announced in September 2022.

[55] Arnett began dating Amy Poehler in 2000, four years after their initial encounter in 1996 when he saw her in an Upright Citizens Brigade performance.