"Datsu Imōto Sengen" centers on the life of Itsuki, a young man who has spent years indulging in the otaku subculture, particularly his obsession with imōto (little sister) characters in anime, manga, and games. His fixation reaches a point where he begins to project these fantasies onto his real-life younger sister, Yuzu, creating an uncomfortable dynamic between them. Yuzu, aware of her brother's unhealthy behavior, decides to confront him and help him break free from his delusions.

The narrative explores Itsuki's journey as he attempts to distance himself from his imōto obsession and reconnect with reality. Yuzu plays a pivotal role in this process, challenging his fantasies and encouraging him to develop healthier relationships. Along the way, Itsuki encounters other characters who either enable or challenge his behavior, including fellow otaku and individuals who represent different perspectives on fandom and personal growth.

The story delves into themes of escapism, the impact of media on personal relationships, and the struggle to balance fantasy with reality. Itsuki's character arc is marked by moments of self-reflection and gradual progress, as he learns to appreciate his sister and others for who they are, rather than through the lens of his otaku fantasies. The series balances humor with more serious undertones, addressing the consequences of unchecked obsession while maintaining a lighthearted tone in its portrayal of otaku culture.