Garfield lives with canine Odie and Jon in a what appears to be a suburban town inhabited by cartoon characters within the Comic Strip World. Garfield and the gang work at Comic studios with other comic characters. The comic strip is made in Comic Strip world, and sent to “The Real World” where it is put in the newspaper. Garfield is tired of the same old jokes his friends crack and is bored with his work and life in Comic Strip World and longs to go to The Real World.
Odie, unwilling to return a prop bone to the Prop Boy, tries to hide it and ends up opening a patch in the screen. The danger alarm is rung, and everyone panics. Eli, the Head Technician of Comic Studios explains to the comic characters that the screen separates Comic Strip World and The Real World, with no way back. Garfield sees his chance to go to The Real World (and eat the hot dogs opposite the news stand) and goes through the screen without anyone noticing. Later on, the comic characters realize Garfield is in the real world, and Eli blocks the patch in the screen that separates the real world by using special tape on it. Odie also winds up in the Real World. Odie gets his bone back and he and Garfield go find some dinner. Garfield meets a cat named Shecky, who invites Garfield and Odie to dinner and a show. As they chat, Odie is chased by a gang of chihuahuas who want his bone. Garfield goes to save Odie, and eventually defeats the chihuahuas. Shecky and the duo head to a fence (which is known as Club Shecky) where the dinner and show is, where they meet two other pets, Waldo and Sheila. Shecky gets dinner by performing a "show" for the people who live in a building. The people who are trying to sleep get annoyed and they start throwing leftover foods at him. After dinner, Shecky brings Garfield and Odie to their new home, an abandoned hotel called Hotel Muncie.
The next day, Garfield finds a newspaper in the trash, and learns his strip will be canceled. Garfield finds an article in the newspaper asking people to audition and replace Garfield. Garfield and Odie head for the place where they are doing try-outs. The judges are not impressed by the others auditioning. Garfield and Odie also fail. The judges are more impressed in Hale and Hardy, a muscular dog and a muscular cat. One of the judges, Sid, decides to give Garfield one more chance: If Garfield's strip isn't back in the paper in 24 hours, he and the judges will have to deal with Hale and Hardy. Garfield has an idea of building a bigger version of a concertina Wally (Neil Ross), another comic strip character, had invented (which has the ability to steal cookies) that can go through the screen back in Comic Studios and shares the idea with his friends back in Comic Strip world. Wally and the other comic strip characters then start building the giant concertina according to Wally's blueprints.
Later that night, Garfield and Odie return to Hotel Muncie. Hale and Hardy sneak in the hotel and go into Garfield, Odie and Shecky's room and tie them up and taunt them before leaving. As they close the door, a candle is knocked over and it sets fire to a newspaper, causing the entire hotel to go on fire. Eli finds out about this and calls everyone to the screen. Wally and the others complete the finishing touches to the giant concertina. Wally then asks for two volunteers to come with him to save Garfield, Odie and Shecky. Billy Bear, another comic strip character who shares a strip with Randy Rabbit, and Jon volunteer to go with Wally to save the three friends, and go through the screen by going into the giant concertina-tunnel built by Wally. They enter the burning hotel through a small hole in the wall and free the three friends, and prepare to escape, but the entire hotel is in flames and the ceiling begins to collapse, blocking the exits. Luckily, Shecky finds a trash cart that they can ride in. Jon, Wally, Odie, Garfield and Shecky jump in and Billy Bear is about to push the cart when Odie realizes his bone is missing and finds the bone lying on a chandelier. Billy Bear pushes the cart and jumps in too and they go down the staircase. Garfield winds up on the chandelier too. The others eventually save Garfield and Odie. The chandelier collapses causing the cart and the chandelier to fall to the ground. The six duck as the cart crashes out of the hotel. The cart's wheel get wrecked, causing the cart to fling the six into the "Bonitanator" and the door of the tunnel closes and disappears and they are transported back to Comic Strip World.
Some days later, Hale and Hardy are shown reading the newspaper that reads that Garfield and Odie are back in the comic strips and express disappointment. Waldo and Sheila are on their own now that Shecky is in the comic strips. The comic characters dance and celebrate the return of Garfield. Unknown to the comic characters, the chihuahuas have also gone through the "Bonitanator", and the film ends with them chasing Odie.
- Frank Welker as Garfield and Hardy
- Gregg Berger as Odie, Shecky and Hale
- Wally Wingert as Jon Arbuckle and Mike
- Audrey Wasilewski as Arlene, Zelda and Betty
- Jason Marsden as Nermal
- Fred Tatasciore as Billy Bear and Waldo
- Stephen Stanton as Randy Rabbit
- Neil Ross as Wally and Charles
- Jennifer Darling as Bonita
- Jajia Baroudi as Sheila
- At Garfield's bedroom, a picture of the June 8, 2003 comic strip (which is smashed by the lamp) is seen.
- Frank Welker, Wally Wingert, Jason Marsden and Audrey Wasilewski become the official voices for Garfield, Jon, Nermal and Arlene respectively. Gregg Berger reprises his role as Odie.
- The book "In Dog Years I'd Be Dead" is seen in The Daily Newspaper Chronicle.
- In the comic strip, Garfield sleeps on the table or floor in his bed-box. In this film, he has his own bedroom.
- Odie talks more English in the film than in the comic strip, such as "My Bone!", "I Don't Know", and "Right."
- Unlike the first two live-action films and The Garfield Show, when Garfield talks, Jon and other humans can understand what he is saying (while in Comic Strip World).
- This is the first full CGI animated film of Garfield, and the first film to be released directly to DVD.
- Lasagna and pizza have never been mentioned in this film. Instead, Garfield favors hot dogs.
- Grimmy from Mother Goose and Grimm and Dagwood from Blondie make cameo appearances.
- This was Arlene's first animated appearance since 1991. This was also the first time Arlene was given a voice in an animated feature.
- When Jon says, "Hot! Hot! Hot!" three times while taking out a pie from a microwave/oven, his lips are out of sync.
- In the same scene, Jon tosses three plates into the air; the last one intersects with the camera.
- When Garfield wakes up, they keep discussing that it is Monday. But when the newspaper goes to print, it says that it is Thursday.
- When Garfield is talking to Wally, the background has Zelda cooking Kat-Kreal Stew. In the next shot, she's serving sandwiches.
- In The Real World, Odie's bone is being chased by Chihuahuas, and after the lamp-post shot, they land flat on the ground near Odie. The computer had very poor animation performance to clear the clay off of the Chihuahuas after they arise from the land and chase after Odie. There are still brown puddles (made of clay), that are on the ground.
- In the fire scene, Jon tries to catch Garfield from the chandelier at the main staircase. When Jon reaches out to grab Garfield, there is no rail on the stairs. It comes back in the very next shot and disappears again after Garfield says, "Need a lift?"
- In the fire scene, after Garfield says, "Need a lift?", Wally is shown smiling, despite being in a dangerous situation.
- Whenever the fire scene is going in slow motion, the fire in the background is not in slow motion.
- When Garfield and Odie are on a fence trying to "leap" into the comic world, Odie's bone disappears in the close up shot and does not come back throughout that scene.