"Kiss Him, Not Me" centers around Kae Serinuma, a high school girl and avid fujoshi who immerses herself in the world of boys' love manga and anime. Her life takes an unexpected turn when her favorite anime character dies, triggering a period of intense grief during which she loses a significant amount of weight. Upon returning to school, her drastic transformation catches the attention of four male classmates: the popular and athletic Yuusuke Igarashi, the reserved and intellectual Shima Nishina, the cheerful and friendly Nozomu Nanashima, and the aloof yet kind-hearted Asuma Mutsumi. Each of them begins to develop romantic feelings for her, leading to a series of comedic and heartfelt interactions.

As Kae navigates her newfound popularity, her primary interest remains in shipping the boys with each other rather than pursuing romantic relationships herself. Her fujoshi tendencies often lead to humorous misunderstandings and exaggerated fantasies about the boys' potential pairings. The story explores themes of self-acceptance, as Kae struggles with her identity and the pressure to conform to societal beauty standards. Despite her weight loss, she remains true to her otaku passions, challenging the notion that external appearance defines one's worth.

The narrative also introduces Megumi Iino, a female classmate who harbors feelings for Kae, adding a layer of complexity to the romantic dynamics. Megumi's presence highlights the series' exploration of diverse romantic possibilities, including same-sex relationships, while maintaining a lighthearted tone. The interactions between the characters are driven by comedic misunderstandings, heartfelt confessions, and moments of personal growth, creating a balance between humor and emotional depth.

Throughout the series, the boys' attempts to win Kae's affection often result in comedic rivalries and exaggerated scenarios, reflecting the over-the-top nature of romantic comedies. However, the story also delves into their individual struggles and insecurities, humanizing them beyond their initial archetypes. Kae's unwavering passion for boys' love serves as a unique lens through which the series examines themes of love, friendship, and self-discovery, making "Kiss Him, Not Me" a distinctive addition to the romantic comedy genre.