After suffering through one hundred rejections from girls he genuinely loved, middle school graduate Rentarou Aijou visits a matchmaking shrine in desperation. To his astonishment, a love god appears and reveals that Rentarou's romantic failures were not his fault but a cosmic error. To compensate, the god promises that in high school, Rentarou will meet one hundred destined soulmates. However, there is a horrific catch the god conveniently forgot to mention: if any of these soulmates fails to enter a romantic relationship with Rentarou, they will die in a fatal accident.

The story is set primarily at a prestigious high school, which later becomes intricately tied to the plot. Rentarou quickly discovers the truth of the god's words when two classmates, Hakari Hanazono and Karane Inda, confess their love for him on the very same day. Hakari is a wealthy, elegant girl with a hidden perverted and physically affectionate side, while Karane is a classic tsundere who cannot hide her true feelings despite her harsh words. Trapped in a life-or-death scenario, Rentarou decides the only logical solution is to date all one hundred of his soulmates, forming what he calls the Rentarou Family.

As the series progresses, Rentarou meets a diverse and increasingly eccentric array of soulmates. These include Shizuka Yoshimoto, a mute bookworm who can only communicate by pointing at words in a book until Rentarou creates a speaking app for her; Nano Eiai, a hyper-logical girl who values efficiency above all else; and Kusuri Yakuzen, an 18-year-old pharmaceutical genius who has shrunk her own body to that of an elementary schooler with a failed immortality drug. The family expands to include Hakari's own mother, Hahari Hanazono. Initially, Hahari tries to break up Rentarou and her daughter, believing him to be a two-timer. However, she falls in love with him upon their first meeting and, to prove her devotion, buys the entire school to become its chairwoman.

Notable narrative arcs involve the development of these complex relationships. One early arc focuses on the rescue of Hakari after her mother locks her away, only to end with Hahari joining the family. A significant storyline involves Kusuri creating a drug that causes the girlfriends to swap bodies, forcing Rentarou to identify each one purely by their mannerisms and leading to chaotic romantic resolutions. Another major arc delves into Shizuka's traumatic past, forcing her to confront her abusive mother about her selective mutism with the full support of the Rentarou Family. Later arcs introduce even more unusual situations, such as battling yokai at school or incorporating a half-Brazilian capoeira expert who is terrified of things she cannot punch. Through every absurd scenario, Rentarou remains committed to his singular goal: ensuring that every single one of his one hundred girlfriends lives a happy, fulfilling life, no matter how chaotic the family gets.