Oswalt is probably best-known to mainstream audiences for the role of Spence in the long-running TV sitcom The King of Queens and for providing the voice of Remy the rat in the Pixar animated feature Ratatouille. He has been a guest on "@midnight". Oswalt also gave critically-acclaimed performances in the independent films Big Fan and Young Adult. In 2016, he won an Emmy Award for Writing for his comedy special Talking for Clapping.
Oswalt is passionate about his love of film and "nerd" culture, a trait he shares with comedian (and long-time friend) Dana Gould. His last name has occasionally been mis-represented as "Oswald".
In the early 1990s, Oswalt appeared in a number of promotional spots and interstitials produced for Comedy Central, many of which appeared during broadcasts of Mystery Science Theater 3000. A series of these featured Oswalt and fellow comedian Blaine Capatch stranded in outer space.
In 2008, Oswalt hosted the MST3K Reunion panel at San Diego Comic-Con.
On October 26th, 2009, Oswalt performed stand-up comedy as the opening act for Cinematic Titantic Live! before a presentation of Danger on Tiki Island at Largo at the Coronet in Los Angeles.
In November of 2015, it was announced that Oswalt would appear in the crowd-funded revival of Mystery Science Theater 3000, playing the role of TV's Son of TV's Frank, henchman to Kinga Forrester (and, presumably, son of TV's Frank). Oswalt was also stated to be a part of the writing staff.Following the announcement, Oswalt tweeted an image of the text exchange between himself and Joel Hodgson, demonstrating his happiness at being involved with the project. Oswalt was later present at the live online telethon for the Kickstarter's end, where he and Hodgson made light of the technical difficulties in the broadcast.