The CGI animation was done at Illumination Mac Guff, with some fantasy sequences animated by Rough Draft Korea.
Garfield is a lazy tabby cat who has an obsession for Italian food (mainly lasagna and pizza) and a strong dislike of Mondays. He spends his time booting his canine roommate Odie off the table, showing very little sympathy over his nerdy owner Jon's failures, hanging around with his mouse friend Squeak, abusing the cute kitten Nermal, and trying to impress his pink-furred girlfriend Arlene. Life is just perfect for Garfield, but soon, a stray cat named Toby comes to the neighborhood. He is enraged because of the tricks Garfield played on him when he was still living in a trash can outside Mamma Leoni's Italian Restaurant where Garfield formerly lived before being adopted by Jon, and wants to get his revenge on Garfield by getting him sent to the pound for life. Upon finding out Toby's whereabouts, Garfield soon learns that his destiny lies in the palm of his paws, and must make alliances with Odie, Squeak, Nermal and Arlene to stop Garfield's own enemy from destroying his life.
- Jason Segel as Garfield, the film's titular protagonist who is a fat orange tabby cat.
- Justin Timberlake as Odie, Garfield's dog roommate whom he has a love-hate relationship with.
- Timberlake also voices Squeak, a house mouse whom Garfield refuses to eat.
- Amy Poehler as Arlene, Garfield's girlfriend.
- Kath Soucie as Nermal, a gray kitten who constantly boasts about his cuteness, which annoys Garfield.
- Rowan Atkinson as Toby, a stray bengal cat who is the main antagonist of the film.
- Ben Stiller as Jon Arbuckle, the owner of Garfield and Odie.
- Reese Witherspoon as Liz Wilson, Jon's girlfriend.
- Kevin Hart as the Mailman, an unlucky mailman who Garfield likes to torment.
- Seth Green as the spiders, unlucky arachnids who fall victim to Garfield's swatting. They make minor appearances in the film.
- Josh Cooley as Binky the Clown, a clown who stars in Garfield's favorite TV show of the same name.
The film was released to DVD on October 1, 2021 and to Blu-Ray on November 20, accompanied by the extras "Peace and Quiet" (the first episode of Garfield and Friends), "From the Oven" (a Season 1 episode of The Garfield Show), and the exclusively-made short "Bath Time".
- A U.S. Acres strip can be seen on Jon's newspaper in one scene. Conditionally, Illumination also produced a film based on U.S. Acres the following year.
- Compared to the critically-acclaimed CGI animation identical to Jim Davis' artwork seen in Garfield Gets Real, Garfield's Fun Fest, Garfield's Pet Force and The Garfield Show, the CGI in this film is more similar to the one in Illumination's other films, due to Illumination Mac Guff doing the animation.
- Originally, the film was supposed to have animation identical to Jim Davis' artwork, but Chris Meledandri felt it would be not necessary for it.
- Illumination logo sequence: Stuart the Minion spots a tray of lasagna on the floor and begins to eat two pieces. Soon Garfield and Odie come, wielding their utensils and wearing a napkin, and sit down to eat lasagna, only to see Stuart touching their food. Sheepishly, Stuart asks (in Minionese) if they could eat together, but Garfield, unhappy that the Minion is touching the lasagna, throws a piece in his face, then he and Odie satisfyingly proceed to eat their food while Stuart leaves rejected.
- This is the second Illumination Entertainment film to have fantasy sequences animated by a different studio (Rough Draft Korea in this case), the first being 2015's Minions.
- "Friends Are There", the original theme song of Garfield and Friends, is heard twice; first as a ringtone in Jon's phone, then second as a remixed version during the credits.
- Garfield's mouth moves when he speaks, much like in the 2004 Garfield film and it's 2006 sequel Garfield: A Tale of Two Kitties, the three direct-to-DVD Garfield films and The Garfield Show.