Willie Morris as an adult is looking back on his childhood in the early 1940s and how it was colored by his dearly beloved dog, a Jack Russell Terrier whom he had named Skip (Enzo). In the beginning, Willie (Frankie Muniz) is a lonely 9-year old child with a gruff, proud father (Kevin Bacon), a Spanish Civil War veteran, and a charismatic, talkative mother (Diane Lane), a housewife, but he is an only child and small for his age with few friends. His one companion is a young man who lives next door, Dink Jenkins (Luke Wilson), who is the local sports hero in Mississippi. However, when Dink is drafted to go to war, Willie's mother decides to buy him a dog, against his father's wishes, in order that he should have some company.
Willie and Skip become firm friends very quickly. However, Willie gets bullied at school by Big Boy Wilkinson, Henjie Henick, and Spit McGee, until Dink sends him a German helmet and belt from the front line. The other boys demand he play ball in order to win back his belongings. Skip leaps in to help him. That same day, the three boys talk Willie into spending the night in a graveyard, where they claim a witch is buried. If he stays there, he gets to join their gang and also keep the ball Dink Jenkins signed for them, and if not, he has to give them his German helmet. Willie stays there for a number of hours, until he hears two moonshiners who are loading crates into a crypt. Skip jumps on Millard, one the moonshiners, until the second one, Junior, comes at him with a spade. Willie uses a slingshot to hit Junior in the nose with an acorn and attempts to escape the graveyard with Skip. They are soon captured by Junior. He tells Willie not to move before sunrise or he will kill Skip. Then the two men leave. The three boys return in the morning and accept Willie into their group for spending the night in the graveyard.
The narrator then goes on to explain various changes in his life. Skip, having always been a friendly dog, is known by everyone in the town, including black people, significant because Mississippi was still segregated at the time. Skip leads Willie through the best parts of his life; his boyhood days. Thanks to Skip, Willie now has three friends, and a girlfriend, Rivers.
Skip is there for him when Dink gets home, shell-shocked and a drunkard since discharged from the army. However, when Willie’s first ball game comes along, Skip and Willie have their first falling out.
Dink promised to come along but does not bother. Since the war he has found competitions do not matter to him anymore, and Willie is so upset by this that his game is ruined. Skip, wanting to cheer him up, runs onto the field and sits wagging his tail, refusing to leave. Becoming increasingly frustrated, Willie hits him across the muzzle and he runs away.
After the game, a devastated and tearful Willie is unable to find his dog. Unbeknownst to him, Skip had returned to the crypt, and been accidentally shut in the grave where moonshine alcohol was being stored. Dink, however, after explaining that he had been scarred by having to kill in the war, tells Willie nothing is ever lost for good and goes out to help him find Skip. As Willie searches in the graveyard, he hears Skip's barks, and can see that Junior is about to strike Skip with a spade. He runs to save him, but there is a thump and a whimper. Dink arrives, and manages to eject the two moonshiners, telling Junior that he'd better hope that Skip lives, but it is uncertain as to whether Skip will survive.
As the family and friends gather in solemnity in the vet's waiting room, Willie weeps over his dog’s vet bed, telling him everything he ever should have done; that he will never have a true friend more dear like him again. Skip awakens, licking his hands and face.
The film concludes with Willie explaining his friendship with Skip, that he had been an only child and Skip an only dog. When Willie leaves to go to Oxford University in the United Kingdom, Skip remains with Willie's parents, sleeping in Willie's old room, and finally dies, being buried under the elm tree. The closing line adds, "That wasn't totally true. For he really laid buried...in my heart".
The film was theatrically released on March 3, 2000, by Warner Bros. and was released on DVD, VHS, VCD, and Blu-ray from 2000 to 2006 by Warner Home Video.
The film opened at #3, grossing $7 million. It ended up grossing $35,512,760 worldwide, making it a major box office success recouping its $4.5 million budget. It also was Warner Bros. first majorly successful family film since Space Jam in 1996. The film came in at number 4 of Variety's "dollar for dollar" most profitable films of the year 2000. The movie remained in Variety's Top Ten video sales charts for five months after its video release. My Dog Skip won the Broadcast Film Critics Award for "Best Family Film" for the year 2000, Silver Medal Giffoni Film Festival Award, Best Cast Young Star Awards, Silver Angel Award winner, ArkTrust Genesis Award, and the Christopher Award for Best Family Film. It was filmed in the city of Canton, Mississippi; the local visitor's center offers tours showing memorabilia used in the film.
A few blocks away from this museum is the house used in the film (private), with a sign in front saying "Skip's House". Movie Room Reviews gave the film 4 stars and said "The film made to delight animal lovers, children, and grandparents". The author of the book, Willie Morris, suffered from a heart attack right after the film was completed in 1999. Morris saw a preliminary screening of the film in New York and praised it as "an absolute classic". Morris died a couple of days later and never saw the final version. The film is dedicated to his memory.