Oswalt was born January 27, 1969, in Portsmouth, Virginia, the son of Carla (née Runfola) and Larry J. Oswalt, a career United States Marine Corps officer. He was named after General George S. Patton. He has one younger brother, Matt Oswalt, a comedy Writer best known for the YouTube web series Puddin'. While he was a military brat, his family lived in Ohio and Tustin, California, before settling in Sterling, Virginia. He is a 1987 graduate of Broad Run High School in Ashburn, Virginia, and subsequently graduated from The College of william & Mary, where he majored in English and was initiated into the Alpha Theta Chapter of the Phi Kappa Tau Fraternity.

Oswalt began performing stand-up comedy on July 18, 1988. After writing for MADtv and starring in his own 1996 comedy special for HBO, he went on to garner notable roles in films and television shows. His most prominent and long-running role was as Spence Olchin on The King of Queens. His first starring film role was as the voice of Remy, the lead character in the 2007 Pixar film Ratatouille. He has also appeared in smaller roles in such films as Magnolia and 22 Jump Street.

Oswalt made his acting debut in the Seinfeld episode "The Couch" and has since also appeared in the superhero film Blade: Trinity (2004), starred in the comedy-drama film Big Fan (2009), co-starred alongside Charlize Theron in Young Adult (2011), and starred in the comedy series The Heart, She Holler (2011–2014). He currently narrates the sitcom The Goldbergs (2013–present) as the adult Adam F. Goldberg, stars in the 2017 revival of Mystery Science Theater 3000, voices the title character in the crime comedy series Happy! (2017–present) and co-stars as Principal Ralph Durbin on the sitcom A.P. Bio (2018–present).

Oswalt married true crime Writer and Journalist Michelle McNamara on September 24, 2005. They had one daughter together, Alice, born in 2009.

Oswalt wrote the comic book story "JLA: Welcome to the Working Week", a backup story in Batman #600; a story for Dwight T. Albatross's The Goon Noir #01 and a story for Masks: Too Hot for TV. Expanding his voice Artist repertoire, he began voicing the villainous character "Tobey" on PBS Kids GO! series WordGirl in 2007. He also appeared on the Comedy Central Roast of william Shatner. In August 2007, he appeared on the Comedy Central Roast of Flavor Flav. In 2007, he appeared on an episode of SpongeBob SquarePants, "The Original Fry Cook", as Jim. In 2008 Oswalt moderated a reunion panel of the Mystery Science Theater 3000 cast at the San Diego Comic-Con International.

In November 2009, an animated video of Patton's take on New Song's Christmas Shoes was posted on YouTube. The track isn't found on any albums. The audio is claimed to be recorded at Lisner Auditorium in Washington DC.

Oswalt's album, Patton Oswalt: Finest Hour, was released on September 19, 2011. The extended and uncensored DVD of this special was released in April 2012, a few days after its television premiere on Comedy Central.

In 2013, he teamed up with PETA and spoke out against chaining pet dogs, and sent a letter to the mayor and members of the city council of Newport News, Virginia, urging them to ban the practice.

Oswalt's comedy special Tragedy Plus Comedy Equals Time was to be released on January 16, 2014, via online movie streaming website Epix but was pushed back by the company for unknown reasons. However, it did premiere on Comedy Central on April 6 and became available for purchase on April 8 in both DVD and CD format.

In November 2015, Oswalt was announced to be the second "Mad" to appear in the reboot of Mystery Science Theater 3000, as the son of Frank Conniff's character TV's Frank.

On April 21, 2016, McNamara died in her sleep in the family's Los Angeles, California home. Her death was attributed to a combination of a previously undiagnosed heart condition and complications from prescribed medication (Adderall, Xanax and Fentanyl). The season 3 finale of The Goldbergs was dedicated to her memory. On August 1, 2016, Oswalt announced that he had been working to complete McNamara's non-fiction book on The Golden State Killer, which was left unfinished at the time of her death. In September 2017, Oswalt announced that the book, titled I'll Be Gone In The Dark, was scheduled for release on February 27, 2018 and was subsequently available for preorders.

He was confirmed to be engaged to Actress and legal mediator Meredith Salenger in July 2017. They were married in November 2017.