Garfield is an overweight, lazy and free-spirited orange cat who lives with his owner Jon Arbuckle in a cul-de-sac in Ferndale, a suburb of Detroit, Michigan. Garfield passes his time by antagonizing Jon and teasing his aggressive neighbor, Luca, a Doberman. Aside from Jon, Garfield maintains an unlikely friendship with a helpful mouse, Louis. Garfield also socializes with his fellow neighborhood cats, including Garfield's stooge Nermal and Arlene.

Jon has made a habit of bringing Garfield to the veterinarian, in order to see vet Dr. Liz Wilson (whom he is in love with). Jon tries to ask Liz out, but due to a misunderstanding, Jon is given custody of a dog named Odie, who is lovable, playful and friendly. Regardless, Jon and Liz begin dating. Garfield however, begins to dislike Odie and tries to get rid of him by getting revenge. Odie is brought to a canine talent show, where Liz is a judge. Garfield gets involved in an altercation there with other dogs, which moves Odie to the center of the ring, where he begins dancing to "Hey Mama" by the Black Eyed Peas.

Odie's improvised performance is a hit. A local television host, Happy Chapman, known for his cat "Persnikitty", who also is a judge of the dog show, is impressed with Odie, and offers Jon a television deal for Odie, but Jon declines, making Happy more determined than ever to upstage his brother. When Garfield comes back, he hits a ball in frustration, causing a chain reaction that trashes Jon's house. When Jon finds his house in ruins later, he forces Garfield to sleep outside for the night. Heartbroken, Garfield sadly sings ("New Dog State of Mind"). When Odie comes out to comfort Garfield, he gets inside and locks Odie out on purpose. Nermal and Arlene witness this as Odie runs away where he is then picked up by an elderly woman named Mrs. Baker. Jon searches with Liz for Odie while the neighborhood animals angrily accuse Garfield for locking Odie out and making him run away the night before while Garfield states that he only was protecting his turf and never wanted Odie to run off.

Meanwhile, Chapman, who is revealed to be allergic to cats, jealous of his news reporter brother Walter J. Chapman, and wants to be more successful than him by performing on TV show Good Day New York, and his assistant Wendell find a notice Mrs. Baker created of Odie and, recognizing the lucrative possibilities, claim Odie as Happy's own, instantly kidnaps Odie, and gives Mrs. Baker an autograph. When Garfield sees Odie on television and hears Chapman announce he and Odie are going to New York City, Garfield sets out to rescue Odie. Jon discovers Garfield is also missing so he tells Liz to start searching for him and Odie. Garfield gets into the broadcast tower via the air vents but he is blown around violently. Garfield finds Odie locked in a kennel, but Chapman enters and secures a shock collar to Odie, which, when activated, releases an electric discharge that forces Odie to perform tricks.

Chapman heads for the train station with Garfield in close pursuit. However, an animal control officer catches Garfield, mistaking him as a stray. Meanwhile, Mrs. Baker tells Jon that Chapman took Odie, making him believe Garfield was taken by Chapman too, Jon and Liz race to Telegraph Tower and then to the train station, after learning Chapman has left. At the same time, Garfield is released from the pound by Chapman's abandoned feline star Persnikitty, who is really named Sir Roland, along with the other animals. Chapman boards a New York-bound train, with Odie in the luggage car. Garfield arrives only to see the train depart. Garfield sneaks into the train system control room and frantically switches the tracks, leading to an impending train wreck. Garfield hits an emergency control and causes the train to return to the station. Garfield frees Odie and they exit the train. However, Chapman chases them and eventually corners the two in a suitcase area. Chapman threatens Odie with the shock collar, but is stopped by Garfield's friends and animals from the pound, led by Sir Roland. They swarm and attack Chapman, allowing Odie and Garfield to escape.

The shock collar is now on Chapman, who gets shocked. Jon and Liz arrive to reclaim the animals and find Chapman disoriented. Jon punches Chapman for stealing "both" his pets in the first place (Garfield saying that he wasn't stolen and that he was doing the rescue work), and leaves with Liz and the two animals. Chapman is arrested for his supposed involvement with the trains, as well as for abducting Odie. Garfield regains the respect of his animal friends as a hero. Back at home, Liz and Jon form a relationship, and Garfield learns a lesson about friendship.

Two years after the events of the first film, Jon Arbuckle plans to propose to his girlfriend, veterinarian Dr. Elizabeth "Liz" Wilson, who is going on a business trip to London. Jon follows Liz to the United Kingdom as a surprise; after escaping from a kennel, Jon's two pets, Garfield and Odie, sneak into Jon's luggage and join him on the trip. Garfield and Odie break out of the hotel room due to boredom, and subsequently get lost in the streets of London.

Meanwhile, at Carlyle Castle in the English countryside, the late Lady Eleanor Carlyle's will is read by the solicitors, Mr. Hobbs, Mr. Greene and Mrs. Whitney. She bequeaths Carlyle Castle to Prince XII, her beloved cat who lives a strong life of luxury, and bears a strong resemblance to Garfield. This enrages the Lady's greedy nephew, Lord Manfred Dargis, who will now only receive a stipend of £50 a week and inherit the grand estate once Prince passes away. Lord Dargis traps Prince in a picnic basket and throws him into the river. Garfield inadvertently switches places with Prince after Jon finds Prince climbing out of a drain and takes him to the hotel after mistaking him for Garfield, while Prince's butler, Smithee, finds Garfield in the street and takes him to Carlyle Castle after mistaking him for Prince.

In the grand estate Garfield is residing in, he receives a great deal of special treatment, including a butler and a group of four-legged servants and followers, including Prince's loyal bulldog servant, Winston. Garfield teaches his new animal friends how to make lasagna, while Prince learns to adapt to his new life with Jon. Dargis sees Garfield and thinks Prince has come back. If the solicitors see Prince/Garfield, they will not sign the estate over to Dargis, who secretly wants to destroy the castle and barnyard and kill the animals to build a spa resort, causing Miss Abby Westminster, another solicitor, to get suspicious of him. Dargis makes many attempts to kill Garfield, including one involving a merciless yet dim-witted Rottweiler named Rommel.

Eventually, Garfield and Prince meet each other for the first time and they convince the animals to help them defeat Dargis. Jon and Odie discover the mix-up and go to the castle, which Liz is coincidentally visiting. Garfield and Prince taunt Dargis, whose plan is exposed, and they are seen by the solicitors. Dargis barges in, holding a blunderbuss and threatening the solicitors if they do not sign the papers giving him ownership of the estate, and also taking Liz hostage. Jon attempts to force Dargis to release Liz by holding a crossbow at him, only for Dargis to threaten to kill Jon for getting involved in the first place. Garfield and Prince, with the help of Odie and Jon, save the day while Smithee alerts the authorities and Dargis is arrested for his crimes. Garfield, who had been trying to stop Jon from proposing to Liz, has a change of heart: He helps Jon propose to Liz, and she accepts.