Miles Halter leaves his home in Florida to attend Culver Creek Preparatory High School in Alabama for his junior year. He uses François Rabelais’s last words—"I go to seek a Great Perhaps"—as his argument for choosing boarding school at such a late age. Miles is fond of reading biographies, and particularly of memorizing the last words of famous people.
Soon after arriving at Culver Creek, Miles meets his roommate, Chip "The Colonel" Martin. The Colonel nicknames Miles "Pudge", due to Miles's slender physical appearance. He then introduces Pudge to his friends Takumi Hikohito and Alaska Young. Takumi is a gifted MC/hip-hop enthusiast, and Alaska Young is a beautiful, but emotionally unstable, girl. After hearing Pudge's obsessions with famous last words, Alaska informs him of Simón Bolívar's final words: "Damn it. How will I ever get out of this labyrinth!" Miles asks her what the labyrinth is and the two make a deal: if Pudge figures out what the labyrinth is, Alaska will find him a girlfriend.
On his first night at Culver Creek, Pudge is kidnapped and thrown into a nearby lake by the Weekday Warriors, a group of rich Birmingham-area students who attend Culver Creek. The Colonel, Alaska, and Takumi explain that the Weekday Warriors hate them because they blame the Colonel and his friends for the expulsion of their friend Paul. However, Takumi insists that they are innocent because their friend Marya was also expelled with Paul. Later, Alaska admits that she told on Marya and Paul to the dean of the school, Mr. Starnes, to save herself from being punished. Alaska sets Pudge up with a Romanian classmate, Lara. Unfortunately, Pudge and Lara have a disastrous date, which ends with Pudge having a mild concussion and throwing up on Lara's pants. Alaska and Pudge grow closer and he begins to fall in love with her, although she insists on keeping their relationship platonic.
The Colonel and Alaska decide to pull a series of pranks in a row to intimidate the Warriors. They set off a series of firecrackers near Mr. Starnes' house, which causes him to leave the building to investigate the noise. Then, Alaska and the Colonel sneak inside and use Mr. Starnes' computer to send out fake progress reports to the Warriors’ parents. Finally, Lara puts blue hair dye in the Warrior's shampoo and hair gel. The gang celebrates their victory by drinking and partying at the old barn by the school. While inebriated, Alaska tells her friends about her mother's death from an aneurysm when she was eight years old. She admits that she still feels guilty for not calling 911, even though she did not understand what was happening at the time. Pudge figures that her mother's death made Alaska impulsive and rash. He concludes that the labyrinth was a person's suffering and that humans must try to find their way out.
When they return to school, the Colonel and Alaska celebrate their successful pranks by drinking every night of the next week. On the last night of these 'celebrations', Alaska and Pudge kiss and are about to have sex. However, she is too sleepy to continue and asks to leave it "to be continued". Pudge agrees and they fall asleep together. In the middle of the night, Alaska receives a phone call which causes her to go into hysterics. She insists that she has to leave. Pudge and the Colonel agree to help her leave the school premises by distracting Mr Starnes with another set of fireworks. A drunk Alaska drives away and gets into a car accident that kills her instantly. In the morning, Mr. Starnes holds an assembly to inform the students of Alaska's death. The Colonel and Pudge are devastated and blame themselves for her death. However, they learn that Alaska might have deliberately crashed her car as a suicide attempt. If she did commit suicide, then the Colonel believes she was selfish in making them help her. The Colonel insists on questioning Jake, her boyfriend, but Pudge refuses, fearing that he might learn that Alaska never loved him. They argue and the Colonel accuses Pudge of only loving an Alaska that Pudge made up in his head, not who Alaska really was. Pudge realizes that he did only love an idealized version of Alaska and the two make up.
As a way of celebrating Alaska's life, Pudge, the Colonel, Takumi, and Lara team up with the Weekday Warriors to hire a male stripper to speak at Culver's Speaker Day. The whole school finds it hilarious, including Mr. Starnes. Pudge finds Alaska's copy of "The General in His Labyrinth" with the labyrinth quote underlined and notices the words "straight and fast" written in the margins. He remembers Alaska died on the morning after the anniversary of her mother's death and concludes that Alaska felt guilty for not visiting her mother's grave. In her rush, she might have been trying to reach the cemetery or might have committed suicide out of guilt. On the last day of school, Takumi confesses in a note that he was the last person to see Alaska.