The movie begins by introducing Garfield as a fat lazy cat (voiced by Bill Murray) who lives with Jon Arbuckle (Breckin Meyer). Garfield wakes up from a good night's sleep and awaits a tasty breakfast.When John dosen't wake up after trying to cuddle him he breaks John's grip on him saying he's "trying to avoid his duties".He cannonballs off a shelf. After switching his liver flavored cat food with Jon's corned beef hash and after flushing the toilet while he is in the shower (tormenting Jon as usual), Garfield spots a pie outside on the neighbor's window. He tricks the Doberman Pinscher Luca (voiced by Brad Garrett) in order to get the pie and tangling his leash around many bushes and ceramic ducks. He also tricks his dimwitted neighbor cat Nermal (voice of David Eigenberg) to tip over a milk bottle through a series of things you find around the house e.g. pots, a bucket in which Nermal has to get in so Garfield's trick works for Garfield every morning.

After walking the cul-de-sac, Jon spots a mouse and counts on Garfield to get it. Garfield refuses and Jon runs after the rodent. He then trips on one of Garfield's toys and says "What good is it to have a cat, if it can't catch a mouse". Garfield then runs outside and catches up to the mouse. The mouse turns out to be Garfield's best friend and his name is Louis (voiced by Nick Cannon) and he was warned by Garfield that he should not run around the house when Jon is home. Jon walks out after Garfield and sees Louis in his mouth. Jon is proud of the tabby cat and when he leaves Garfield spits him out and spares his life. He only did it so Jon wouldn't hurt him.

At the telegraph tower, Happy Chapman (Stephen Tobolowsky), the star of a Saturday morning show, is sick of cats (because of his allergies) and wishes for a dog star along with him, and to outdo his more successful twin brother Walter, a news anchor. After his show, Jon comes home with some food he bought at the store. Garfield pigs out of the lasagna trays and Jon is terribly disappointed. Garfield is brought to the vet (Garfield previously thought he was going to Chuck E Cheese's, Wendy's, Taco Kitty, and Olive Garden), with Jon and is checked out by Dr. Liz Wilson (Jennifer Love Hewitt), a nice and attractive veterinarian and Jon's high school crush. Jon tries to ask her out when a dog is brought in. His name is Odie and Liz asks Jon to take care of Odie or he will survive on his own. Garfield comes out of the vet and sees Odie in the car, and Liz ends up asking Jon out.

Garfield is not very happy, needless to say, now that a dog is running amuck in the house, sitting in his chair, getting the paper, and sleeping beside Jon when Garfield is not allowed to. To make matters worse, Liz shows up and Jon, with Odie, leave to go to the town dog show, and Garfield chases after them. At the dog show (where Liz is a judge) and where Jon is in the audience with Odie, Garfield unwittingly walks right into the show, is spotted by the dogs competing in the show and runs away with the dogs in hot pursuit. The music goes on and Odie leaps out of Jon's hands and attempts to dance (just as when Garfield was dancing back at the house). The judges are impressed as well as the audience. Garfield succeeds in escaping and Odie is rewarded by Happy Chapman (who is also a judge). He says Odie may have a future in television, but Jon turns it down. When a picture for the news paper is taken, you can see Happy looking greedily at Odie.

Garfield hangs on under Liz's truck on the way back, and Jon and Liz plan a dinner on Sunday. Garfield is very angry because Odie got all the attention. He smacks a ball which causes everything in Jon's office to move out of place or break and resulting in the house in shambles. Garfield gets kicked out and he watches in the windows how much Jon loves Odie. He sleeps on the porch that night and Odie comes out to comfort him. Garfield is touched, but then hops inside and locks the doggy door, and locks Odie out. Odie runs away and ends up being found by a sweet old lady.

Jon finds out Odie has gone and he feels terrible. After putting up posters around town, Liz arrives for the dinner, Jon cancels the dinner and tells Liz about Odie. Jon and Liz then work to together to find Odie. Meanwhile, Happy Chapman finds a found poster by the old lady and knows it is Odie. He says that "his" dog, Odie is found. He refers as a family name, he takes Odie with him and the dog performs on the Happy Chapman show. Garfield sees him and Happy announces that he and Odie are going to New York by train for a big performance. Garfield attempts to show Jon, but the show goes to a Wendy's commercial. Garfield then sets out on a mission to rescue the pup.

In the city, Garfield meets Louis again and the mouse guides the fat cat to the Telegraph Tower. Garfield can't go in by the doors, so he climbs the vents and finds Odie in Happy's room. Happy comes in and puts on an inhumane shock collar that with a press of a button, Odie gets a small shock and performs a back flip. Happy then heads to the train station and Garfield follows behind. The Animal Control Guy is caught by Robot and is not thrown in the pound. Jon sees Liz at a clothing store and tells Liz that Garfield has run away too. The couple goes and investigates. Finding a found poster of Odie, the old lady says Odie is Happy Chapman's dog (which is not true) and the two drive to Telegraph Tower.

Garfield, at the pound meets Persnikitty (voiced by Alan Cumming), Happy's last show cat that he threw inside the pound as his real name is Sir Roland. A family arrives to take a cat home for a pet. Sir Roland, Garfield, and 3 other cats are taken and lined up behind a wall. The little girl picks Sir Roland. The old show cat tells Garfield that he will press the red button (which opens all the cages) in order to escape. All the caged animals run like mad cows out in the city.

At the Train Station, while the P.A. said Dallas and San Antonio, Texas from the Texas Eagle Happy places Odie in the luggage cart and sits down for lunch. Garfield just misses the train. Jon and Liz arrive at the Train Station after being told that Happy was going to leave. Garfield then remembers that his train set at home is slightly similar to the train station, so he sneaks into the control room and attempts to stop Odie's train. The tracks get rearranged that all the trains are on the same tracks. Just when the trains are about to collide, Garfield stops all the trains with the press of a certain button. Garfield climbs in the luggage cart after the train returns to the station. He reunites with Odie.

Happy sees Garfield and Odie walk out and is shocked. He runs out and chases them into the station's luggage halls, traps the two animals and threatens Odie with the shock collar. Garfield jumps to the rescue and Happy (not very happy throws) the tabby on some luggage. Garfield gets up and is greeted by the pound animals; they've come to help. The animals corner Happy, and Garfield gives orders to attack as cats scratch, dogs bite and the rats will place the shock collar on Happy's neck. The animals attack Happy and it was a dog pile. The pound animals leave and Garfield and Odie finish off Happy with 2 shocks of the collar. Jon and Liz arrive, Jon furiously punches Chapman, knocking him out. Jon promises the cat and dog to never leave out of his sight. Chapman gets sent away with the police and Garfield is now known as a hero and it was explained in the TV where the cats watch.

Back home, Liz kisses Jon romantically, starting their relationship. Garfield learns friendship and love, and they live as a big happy family....But all that changes when he intentionally pushes Odie off his chair over and over again.

The film closes with Garfield singing and dancing to James Brown's "I Got You (I Feel Good)". He does a split and can't get up.