"Hana-Kimi" centers on Mizuki Ashiya, a Japanese-American girl who transfers to an all-boys high school in Japan to meet her idol, Izumi Sano, a high jump athlete whose performance she admired on television. Disguising herself as a boy, Mizuki enrolls in Osaka High School, where Sano is a student. The series explores her efforts to maintain her secret while navigating the challenges of school life, forming friendships, and dealing with the complexities of her growing feelings for Sano.

Mizuki's roommate, Sano, is initially unaware of her true identity but becomes suspicious over time. Despite his aloof and reserved demeanor, Sano gradually develops a close bond with Mizuki, often protecting her from situations that could expose her secret. Their relationship evolves as Sano begins to uncover Mizuki's true feelings and identity, leading to moments of tension and emotional depth.

The narrative also introduces a diverse cast of characters, including Nakatsu Shuichi, Mizuki's other close friend, who struggles with his own feelings for her, unaware of her gender. Nakatsu's comedic and earnest personality adds levity to the story, while his internal conflict over his attraction to Mizuki creates additional layers of drama. Other characters, such as the strict dorm supervisor Sekime and the eccentric student body president Hokuto Umeda, contribute to the school's dynamic environment, often complicating Mizuki's efforts to keep her secret.

Throughout the series, Mizuki faces numerous challenges, from physical tests of endurance to emotional confrontations, all while balancing her dual identity. The story delves into themes of friendship, identity, and self-discovery, as Mizuki's relationships with Sano, Nakatsu, and others deepen. The series balances comedic moments with heartfelt drama, creating a narrative that explores the complexities of adolescence and the courage it takes to pursue one's dreams and desires.