One evening, when 10-year-old Opal goes to the local Winn-Dixie grocery store, she encounters a big ugly dog running wild in the produce department. To save the dog from going to the pound, Opal makes up a name for the dog—Winn-Dixie—and insists that he’s hers. She leads the dog home to the Friendly Acres Trailer Park where she and her daddy, “the preacher,” live. Opal explains to Winn-Dixie that she and her daddy recently moved to Naomi, Florida so that he could become the preacher of the Open Arms Baptist Church in town. Because he spends so much time focused on the work of being a preacher, Opal refers to him as “the preacher” in her mind. She also often thinks of him as a turtle retreating into his shell to avoid thinking about sad things. Fortunately, Winn-Dixie makes a good impression on the preacher, and he allows the dog to stay.
Opal takes Winn-Dixie outside to bathe him. As she cleans him, she tells him everything she knows about her Mama. It isn’t much: Mama left seven years ago, and according to the ladies at church, the preacher still hopes that she’ll come back. Opal wants to know more about her, but she’s afraid to ask. Winn-Dixie raises his eyebrows and sneezes in response, so Opal agrees to ask the preacher to tell her more. Back inside, Opal does just that. The preacher surprisingly agrees to Opal’s request to tell her 10 things about Mama. He shares that she was a fun-loving woman who loved stories and growing things. However, she also hated being a preacher’s wife and was an alcoholic. His final fact is that Mama loved Opal. Opal points out that Mama still left her, but the preacher corrects her that Mama left both of them. Opal goes to her room to memorize the list.
Winn-Dixie quickly becomes a part of the family. He gets to go everywhere with Opal and the preacher, even to church, as he howls if he’s left alone. The first time he attends church, he catches a mouse to applause from the congregation. During the silent prayer, Opal tells God that she’s lonely since none of the other kids want to be friends with her, and she wants to tell Mama the story of Winn-Dixie catching the mouse.
Opal spends a lot of her summer at her local library. Winn-Dixie waits outside and looks in the windows. One day, Opal hears a scream and discovers the elderly librarian, Miss Franny Block, cowering because the bear “came back.” Opal infers that Miss Franny is talking about Winn-Dixie, assures the old lady that he’s just a dog, and brings Winn-Dixie inside so they can listen to the story of the time a bear entered the library. When Miss Franny is done telling the story, she says sadly that there’s no one alive who also remembers the incident—all her friends are dead. Opal suggests that she, Winn-Dixie, and Miss Franny be friends, thereby making her first friend in Naomi. When a “pinch-faced” girl named Amanda comes in and demands another book, Miss Franny winks at Opal.
As Winn-Dixie starts to look healthier, Opal decides he needs a collar. She goes to Gertrude’s Pets and selects an expensive red leather set, but the employee, Otis, awkwardly refuses to let Opal work out a payment plan. Instead, he agrees that Opal can work for the set by cleaning the shop, but only if Gertrude the parrot likes Winn-Dixie. Surprisingly, she does. Outside the shop, Opal bumps into Sweetie Pie Thomas, a five-year-old from church. Sweetie Pie says she loves Winn-Dixie and wants a dog just like him. She also invites Opal to her sixth birthday party in September. Opal feels happy.
One day, as Opal rides home from Gertrude’s Pets, two boys named Dunlap and Stevie ride behind her, whispering. She thinks they look like “bald-headed babies” since their heads are shaved during the summer. Suddenly, Winn-Dixie takes off and leaps a gate into an overgrown garden. Stevie insists that the witch is going to eat Winn-Dixie, so Opal insults the boys and enters the garden. She discovers Winn-Dixie eating peanut butter out of the hand of a laughing old woman. The woman doesn’t look like a witch at all. She introduces herself as Gloria Dump and offers to make Opal a peanut butter sandwich. As they eat, Gloria explains that she’s nearly blind, so she needs Opal to share everything about herself so that she can get to know her without seeing her. Opal tells Gloria everything. When she’s finished, Gloria suggests they plant a tree to see if Opal has a green thumb like Mama. The tree doesn’t look like a tree and Gloria doesn’t know what it is, so she calls it a “wait-and-see tree.” Gloria tells Opal she can come back any time.
Opal wakes in the middle of the night to Winn-Dixie whining and beating his head against her bedroom door—there’s a thunderstorm raging outside, and he’s terrified. She lets him out of her room, which wakes up the preacher. Winn-Dixie runs and knocks the preacher to the ground. Then, Opal and the preacher sit and watch Winn-Dixie run around the trailer. They discuss that Winn-Dixie has a pathological fear of thunderstorms, but the preacher insists that they need to keep Winn-Dixie safe—he might run away by accident. Opal loves the preacher for saying this and for wanting to protect Winn-Dixie.
Opal arrives early for her first day of work. She enters Gertrude’s Pets and encounters an odd sight: Otis is playing guitar for all the animals, which are out of their cages listening attentively. Otis stops playing when he sees Opal, and the shop plunges into pandemonium. Opal and Otis try to cage the animals until Opal tells Otis to start playing again. With the animals once again subdued, Opal puts them all away. When they’re done, Otis admits that he takes the animals out on purpose—he’s been in jail and knows what it feels like to be locked up. When Opal is finished working, she thinks that the preacher wouldn’t like her working for a criminal. Sweetie Pie meets Opal outside and asks if Otis is a magic man; she saw him “charm” the animals. As Sweetie Pie runs ahead to tell her mama about Otis, Opal wishes she could tell her own Mama everything.
Every day, Opal goes from Gertrude’s Pets to Miss Franny to Gloria’s. Dunlap and Stevie taunt her daily on her way to Gloria’s, so Opal always arrives exhausted. Gloria suggests that Opal is taking things too personally; the boys might want to be friends. Opal isn’t convinced. Opal tells Gloria a new story every day, since Gloria can’t get glasses strong enough anymore to be able to read. One day, Opal decides to share that Otis is a criminal and asks if she should be afraid of Otis. In response, Gloria leads Opal to a tree hung with alcohol bottles. She explains that the bottles are the ghosts of all the things she’s done wrong and admits that she was once an alcoholic; she drank the contents of every bottle on the tree. Gloria insists that even nice people have done bad things and insists that she learned the most important thing—but rather than say what that was, Gloria insists that it’s different for everyone. Opal stares at the tree for a long time, wondering if Mama also has a tree of bottles.
Miss Franny has fits sometimes, and when she does, Winn-Dixie comforts her. Opal thinks that he comforts Miss Franny just like she comforts Winn-Dixie, but Opal is concerned that no one comforts Gloria. She decides to do that herself by checking out Gone with the Wind and reading out loud to Gloria. This prompts Miss Franny to tell Opal and Amanda the story of her great-grandfather Littmus W. Block, who fought in the Civil War. He was thrilled to fight for the cause, but he soon found out that “war is hell”—and when it was over and he returned home, he discovered that his entire family died. When Littmus realized he wanted candy, he vowed to concentrate on making the ugly world sweeter and opened a candy factory in Florida. It manufactured Littmus Lozenges. Miss Franny offers candies to both Opal and Amanda. Both girls agree that it tastes good but somehow also tastes sad. Miss Franny says the candy has a secret ingredient: sadness. Children usually can’t taste it, so both girls must have experienced sorrow. Amanda looks ready to cry, says it makes her think of Carson, and runs away. Opal is perplexed by this, but she takes candies for all her other friends. On her way to Gloria’s, she decides to wave at Dunlap. He waves back.
Gloria remembers eating Littmus Lozenges as a child and is happy to listen to Gone with the Wind. When Opal gives a candy to the preacher that night, he seems to withdraw and says that the candy tastes “melancholy.” He tells Opal that he spoke to Dunlap and Stevie’s mama; Opal needs to apologize for insulting them. When Opal asks, he also shares that Carson was Amanda’s five-year-old brother—but he drowned last summer. Opal stays up for a long time, thinking that life is a confusing mix of sweetness and sadness. Opal gives a lozenge to Otis the next morning. It makes him cry, as it tastes like being in jail. He shares why he was jailed: he wouldn’t stop playing music on the street and knocked out a cop when they tried to make him. Opal understands that Otis is just lonely. Sweetie Pie spits her candy out because it tastes like not having a dog. Opal thinks that everyone is lonely. That afternoon, as she reads about Scarlett’s barbecue in Gone with the Wind, Opal says that the way to fix everything is to throw a party at Gloria’s. Gloria agrees to host, but only if Opal agrees to invite Dunlap and Stevie.
All of Opal’s friends agree to come to the party, even Amanda—though Opal has to promise to work for free for a week to convince Otis. Gloria teaches Opal to make egg salad sandwiches and a punch, and they decorate her garden with candles and crepe paper. The guests arrive and awkwardly greet one another, though Stevie and Dunlap are still missing. Just after Otis arrives, it starts to thunder and pour down rain. In the rush to get everyone and the food inside, Opal realizes that she forgot Winn-Dixie—and now he’s gone. She grudgingly greets Dunlap and Stevie when they arrive. Gloria whispers to Opal that she can’t hold onto anyone who want to leave, but Opal heads out with the preacher to look for Winn-Dixie. They look all over town and as they do, Opal compiles a list of 10 things about Winn-Dixie. She realizes, however, that a list cannot truly describe her best friend. When the preacher insists that they have to stop looking, Opal accuses him of not trying hard enough to keep Mama from running away. The preacher insists that he couldn’t keep her and starts to cry. Opal embraces him and the preacher finally says that Mama isn’t coming back. He says, however, that Mama left one important thing behind when she left: Opal.
Opal and the preacher return to Gloria’s house without Winn-Dixie to find everyone singing. Opal is enraged until Gloria reveals Winn-Dixie, who was hiding under her bed and started sneezing when Otis played his guitar. Everyone became friends while Opal and the preacher were out. Content, Opal slips outside to the mistake tree and tells Mama that she won’t think of her as much going forward, but she knows that Daddy will talk more about her in the future. Then, she checks her wait-and-see tree and discovers that it’s still small, but it’s stronger. Dunlap helps her up, and then they and Amanda head back inside to sing songs and eat Littmus Lozenges with their friends.