"Gakuen Alice" centers on Mikan Sakura, a cheerful and impulsive young girl from the countryside, who transfers to a prestigious and mysterious school called Alice Academy after her best friend, Hotaru Imai, is enrolled there. The academy is an elite institution for children possessing unique abilities known as "Alices," which range from controlling fire to manipulating time. Mikan initially believes she lacks an Alice, but it is later revealed that her ability is the rare and powerful "Nullification Alice," which allows her to neutralize other Alices.

The narrative explores Mikan's adjustment to the academy's rigorous and often harsh environment, where students are categorized into different classes based on their abilities. She befriends a group of classmates, including the aloof and enigmatic Natsume Hyuuga, who possesses the dangerous "Fire Alice," and his protective best friend, Ruka Nogi, who has the "Animal Pheromone Alice." Mikan's relationships with these characters, particularly her growing bond with Natsume, form a central focus of the story.

As the plot progresses, darker elements of the academy's operations come to light. The institution is revealed to be a place where students are exploited for their abilities, often subjected to experiments and manipulation by the academy's leaders, including the enigmatic headmaster, Narumi. Mikan becomes increasingly determined to protect her friends and uncover the truth behind the academy's sinister practices. Her journey involves confronting personal challenges, navigating complex relationships, and challenging the oppressive systems within the academy.

Themes of friendship, loyalty, and resilience are woven throughout the narrative, as Mikan and her friends band together to resist the academy's control and fight for their freedom. The story balances moments of humor and lightheartedness with darker, more intense plotlines, creating a dynamic and engaging narrative. Key arcs include the revelation of Natsume's tragic past, the introduction of Mikan's long-lost father, and the eventual confrontation with the academy's leadership, culminating in a resolution that emphasizes the strength of human connections and the importance of standing up against injustice.