The rare and inexplicable Puberty Syndrome is thought of as a myth. It is a rare disease which only affects teenagers, and its symptoms are so supernatural that hardly anyone recognizes it as a legitimate occurrence. However, high school student Sakuta Azusagawa knows from personal experience that it is very much real. Mai Sakurajima is a third-year high school student who gained fame in her youth as a child actress, but recently halted her promising career for reasons unknown to the public. With an air of unapproachability, she is well known throughout the school, but none dare interact with her—that is until Sakuta sees her wandering the library in a bunny girl costume. Despite the getup, no one seems to notice her, and after confronting her, he realizes that she is another victim of Puberty Syndrome. As Sakuta tries to help Mai through her predicament, his actions bring him into contact with more girls afflicted with the elusive disease.

After surviving the entrance exams, Sakuta Azusagawa has finally enrolled in the same university as his girlfriend, Mai Sakurajima. He is gradually getting used to the unfamiliar environment as he attends student gatherings and makes new acquaintances. Everything seems to be going smoothly until Sakuta's friend and Sweet Bullet idol group member Uzuki Hirokawa begins acting out. With fellow Sweet Bullet member Nodoka Toyohama pleading for his help, Sakuta realizes that he has stumbled upon another case of the inexplicable Puberty Syndrome—Uzuki is feeling pressured by the sudden surge of popularity and rumors of a potential solo career. While Sakuta searches for a solution, another occurrence of Puberty Syndrome gradually emerges from the shadows.