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10-year-old India Opal Buloni has just moved to the fictional small town of Naomi, Florida with her father, a preacher.
While in the Winn-Dixie supermarket, she encounters a scruffy Berger Picard that is wreaking havoc. Opal claims that it is her dog and names it “Winn-Dixie”. Winn-Dixie becomes friends with everyone he encounters, and so she makes some new friends in the process. She also rekindles her relationship with her father, and learns ten things about her mother, who abandoned them seven years ago. Opal describes the preacher as a turtle, always sticking his head into his turtle shell, and never wanting to come out into the real world. This is most likely because of how sad he is about her mother, with whom he is still in love.
One of the people Opal meets is Miss Franny Block, a kind and somewhat eccentric elder librarian, who tells her many great stories, including one involving a bear. Opal also meets Gloria Dump, a blind recovering alcoholic with a tree in her backyard that has beer bottles hanging from it. She calls it a ‘mistake tree’ and the bottles represent the ghosts of all the things she has done wrong. One day, fed up with Winn-Dixie, the landlord of the Bulonis’ trailer park, Mr. Alfred, orders the preacher to get rid of the dog. The preacher calls the animal pound to take Winn-Dixie away, but Opal begs her father to keep her dog. Unable to see his daughter this upset, the preacher tells the pound to return Winn-Dixie, claiming that he is not the same dog he called about.
Opal gets a job at Gertrude’s Pets and befriends a worker there, Otis, a shy ex-convict with a passion for music. She also meets a girl named Sweetie Pie Thomas, who is eager to get a dog like Winn-Dixie. Later, a thunderstorm comes and Winn-Dixie, being pathologically afraid of thunderstorms, runs away. While Opal looks for him, her father wants to give up and she blames him for the loss of her mother and Winn-Dixie running away. But her father explains that he tried very hard to look for her mother. He then admits that he believes that she is never coming back. Later they go back to a party and Otis starts to sing a song on his guitar. Winn-Dixie is heard outside howling along to the song. Everyone, while singing, lets him in and welcomes him back.