Jon Arbuckle (played by Breckin Meyer) plans to propose to his girlfriend Dr. Liz Wilson (played by Jennifer Love Hewitt), who is going on a business trip to London. Jon follows her to the United Kingdom as a surprise; After escaping from the kennel, Garfield (voiced by Bill Murray) and Odie sneak into Jon's luggage and join him on the road trip. Garfield and Odie break out of the hotel room due to boredom, then get lost.
Meanwhile, at Carlyle Castle in the British countryside, the late Lady Eleanor's will is read. She leaves all of Carlyle Castle to Prince XII (voiced by Tim Curry), her beloved cat who looks just like Garfield. This enrages the Lady's nephew, Lord Dargis (played by Billy Connolly), who will now only get the grand estate once Prince is out of the picture. Lord Dargis traps Prince in a picnic basket and throws him into the river.
Garfield inadvertently switches places with Prince: Jon finds Prince climbing out of a drain and takes him to the hotel, while Prince's butler Smithee finds Garfield in the street and takes him to Carlyle Castle.
In the grand estate Garfield is residing in, he receives the royal treatment, including a butler and a team of four-legged servants and followers. Garfield teaches his animal friends how to make lasagna, while Prince learns to adapt to a more humble setting, while in Jon's company. Lord Dargis sees Garfield and thinks Prince has come back - if the lawyers see Prince/Garfield they will not sign the estate over to Dargis, who secretly wants to destroy the barnyand and kill the animals to build a country spa. Dargis makes many attempts to kill Garfield, one involving a unmerciful but dim-witted Rottweiler, Rommel (voiced by Vinnie Jones).
Eventually Garfield and Prince meet each other for the first time (spoofing the Marx brothers' mirror gag). Jon, with the help of Odie, discovers the mix-up and goes to the castle, which coincidentally Liz is visiting.
Garfield and Prince taunt Dargis, whose plan is exposed, and are seen by the lawyers. Dargis threatens everyone if they don't sign the papers to him, taking Liz hostage. Garfield, Prince, Odie and Jon save the day, Smithee alerts the authorities, and Dargis is arrested. Garfield, who had been trying to stop Jon from proposing to Liz, has a change of heart: He helps Jon in proposing, and she accepts.Breckin Meyer as Jon Arbuckle, the owner of Garfield and Odie
Jennifer Love Hewitt as Dr. Liz Wilson
Billy Connolly as Lord Dargis
Ian Abercrombie as Smithee
Roger Rees as Mr. Hobbs
Lucy Davis as Ms. Abby Westminister
Jane Carr as Mrs. Whitney
Oliver Muirhead as Mr. Greene
Bill Murray as Garfield
Tim Curry as Prince XII, a British cat who looks like Garfield
Bob Hoskins as Winston
Rhys Ifans as McBunny
Vinnie Jones as Rommel
Jim Piddock as Bolero
Joe Pasquale as Claudius
Greg Ellis as Nigel
Richard E. Grant as Preston
Jane Leeves as Eenie
Jane Horrocks as Meenie
Roscoe Lee Browne as the Narrator
Rotten Tomatoes, a review aggregator, reports that 11% of 73 surveyed critics gave the film a positive review; the average rating is 3.5/10. The site's critical consensus reads, "Strictly for (very) little kids, A Tale of Two Kitties features skilled voice actors but a plot that holds little interest." On Metacritic, the film has a score of 37 out of 100 based on 20 critics, indicating "generally unfavorable reviews". Audiences polled by CinemaScore gave the film an average grade of "B+" on an A+ to F scale, the same grade earned by its predecessor.
Joe Leydon of Variety gave the film a positive review, saying "Good kitty! Superior in every way to its underwhelming predecessor, Garfield: A Tail of Two Kitties is a genuinely clever kidpic that should delight moppets, please parents -- and maybe tickle a few tweens." Janice Page of The Boston Globe gave the film one and a half stars out of four, saying "You'll only be attracted to Garfield: A Tail of Two Kitties if you're very young, you're very easily entertained, or you just can't get enough of Jim Davis's lasagna-scarfing cartoon cat." Roger Ebert gave the film three out of four stars, saying "Garfield: A Tail of Two Kitties is actually funnier and more charming than the first film." Elizabeth Weitzman of New York Daily News gave the film one and a half stars out of four, saying "Connolly, bless him, throws himself heartily into the task of acting opposite a computer-generated cat given to bad puns and flatulence. Everyone else, however, looks mortified, and can you blame them?" Peter Hartlaub of the San Francisco Chronicle gave the film one out of four stars, saying "The best thing that can be said about Garfield: A Tail of Two Kitties is that the movie isn't quite as bad as its name." Nathan Rabin of The A.V. Club gave the film a C, saying "Two Kitties marks a considerable improvement over its predecessor. It's faster paced and the filmmakers wisely shift the focus away from bland owner Breckin Meyer and onto a menagerie of chattering animals. After a dreadful first entry, Two Kitties elevates the Garfield series almost to the level of mediocrity." Claudia Puig of USA Today gave the film one and a half stars out of four, saying "It comes off like a coughed-up furball: a wan rehash with too many elements of the hard-to-swallow 2004 original."
Garfield: A Tail of Two Kitties grossed $28.4 million in North America, and $113.3 million in other countries, for a worldwide total of $141.7 million. The film opened to number seven in its first weekend, grossing $7.3 million. According to 20th Century Fox, the studio was aware that the film would not make as much as the first, and only made it based on the worldwide success of the first film.
The film was released on DVD on October 10, 2006. The DVD includes a "Drawing with Jim Davis" featurette and two games: Garfield's Maze, and Odie's Photo Album. It also includes a music video, trailers, and footage not seen in theaters.
The film was nominated for two Golden Raspberry Awards in 2006, one in the category "Worst Prequel or Sequel", and one in the category "Worst Excuse for Family Entertainment", but lost to Basic Instinct 2 and RV, respectively.