Junior is a fourteen-year old boy living on the Spokane Indian Reservation in Washington. He was born with hydrocephalus (water in the brain), which has led to a number of health problems. In addition, his large skull, awkward lisp, and thick glasses have made him the victim of bullying from his tribe members - teenagers and adults alike.
Junior's family is poor, Junior explains, and the worst thing about poverty is that he cannot do anything about it. He is devastated when his pet dog, Oscar, becomes ill from heat stroke and his family does not have enough money for a veterinary visit. The only way to put Oscar out of his misery, then, is for Junior's father to shoot the poor creature. Junior runs to his friend Rowdy, who attempts to cheer him up by suggesting they visit a local powwow. There, a group of drunk men beat Junior up. To retaliate, Rowdy cuts the eyebrows and ponytails off Junior's attackers after they pass out.
At school, Junior is one of the few students who is genuinely interested in learning. He is excited to start reading his geometry textbook until he opens the cover and realizes that he is supposed to be studying from the same exact book his mother used when she was in high school. Frustrated with the lack of educational resources available on the reservation, Junior hurls the textbook across the room and accidentally hits his teacher, Mr. P., in the face.
Junior is suspended from school, and Mr. P. comes to visit him at home. Instead of reprimanding Junior, Mr. P. shockingly apologizes instead for how he and other white teachers have systematically tried to force Indian children to assimilate into Western culture and encourage them to forget their own roots. He can see Junior's potential and tells his young student that the only way he will succeed is by getting off the reservation. Junior takes Mr. P.'s advice and decides to transfer to Reardan, a school in a wealthier district about twenty miles away. Junior's parents are supportive of his decision, but Rowdy is furious - he starts to cry and then punches Junior in the face.
Junior feels like a complete outsider at Reardan. He admires a pretty girl named Penelope, but she makes fun of his name. Roger, a star athlete, makes a sickeningly racist joke, for which Junior punches him in the face. Instead of fighting back, Roger walks away bewildered, calling Junior "an animal." Junior goes to his grandmother for advice, and she tells him that Roger will respect Junior now that he has stood up for himself. She turns out to be right.
On Halloween, both Junior and Penelope dress up as homeless people, although Junior jokes that his costume is not too far off from the clothing he usually wears. In order to impress his crush, Junior offers to trick-or-treat for money that they can donate to charities aimed at helping the homeless. Junior ends up raising ten dollars on the reservation, but bullies in costume beat him up and steal the money. He tells Penelope what happened and she is sympathetic, saying she will still make the donation in both their names.
Unable to secure Penelope's affections, Junior soon forms a friendship with Gordy, who is academically inclined. Their connection is based on studying; Gordy teaches Junior how to retain knowledge and perform better on exams. At home, Junior discovers that his sister, Mary, has married a man that she met at the casino and has run off to Montana. Later, Mary sends Junior an email describing how happy she is.
By Thanksgiving, Junior is lonely. Rowdy still refuses to speak to him, so he draws a cartoon of the two of them as superheroes and delivers it to Rowdy's home. Back at school, Junior hears Penelope vomiting in the bathroom and finds out that she is bulimic. Junior offers his support and Penelope opens up to him. The two of them finally become friends, which makes other students at Reardan accept Junior, as well.
Junior and Penelope's relationship becomes stronger and he takes her to the Winter Formal. He is embarrassed about having to wear his father's outdated suit, but his classmates find it cool and retro. At the diner after the dance, Junior reluctantly borrows money from Roger to pay for Penelope's meal. That night, Penelope realizes that Junior does not have any money and that he often walks home from school. She asks Roger to give him a ride, and Roger ends up driving Junior home many nights after that.
Junior decides to try out for the Reardan basketball team, and, against the odds, makes it onto the varsity squad. Reardan's first game of the season happens to be against Wellpinit, the reservation school. At the gym, all the spectators from the reservation turn their backs on Junior, whom they see as a traitor to his tribe. During the game, Rowdy jumps Junior violently and knocks him unconscious. However, Junior's Coach is impressed with his tenacity and they form a bond.
Over the Christmas holidays, Junior's father gets drunk and disappears with all the family's money. When he returns from his drinking binge, he gives Junior his only present: a soggy five dollar bill. A larger tragedy hits Junior's family soon thereafter, when Grandmother Spirit is killed by a drunk driver in a hit-and-run. Over two thousand Indians come to her funeral, as she was a highly respected member of the community. Soon after that, Eugene, Junior's father's best friend, is shot in the face during a drunken brawl. As a result of these tragedies, Junior misses a lot of school, but his fellow students support him when a teacher tries to chastise him for his absences.
In the second matchup between the Reardan and Wellpinit basketball teams, Junior is prepared and determined. He leads his team to victory but afterwards, feels ashamed when he sees his former classmates' faces. He alone knows how troubled their lives are; not a single one of them will go to college. Junior emails Rowdy an apology for his behavior, and Rowdy responds. They begin to banter like they used to. Then, tragedy strikes again: Mary dies in a fire after passing out drunk in her trailer. Junior is devastated.
Despite all of the trials he has faced during his freshman year at Reardan, Junior gets mostly As in his classes. He accompanies his parents to the cemetery so they can "spend time" with Grandmother Spirit, Mary, and Eugene. Junior thinks about all the people he has loved who died alcohol-related deaths, and all the Spokanes who will die in the future.
During summer break, Rowdy comes to visit Junior under the pretense that he is bored. The two play basketball, symbolizing the rekindling of their friendship.
