"Oniichan no Koto Nanka Zenzen Suki Janain Dakara ne—!!" centers on the life of Nao Takanashi, a high school student who lives with his younger sister, Nao. The series begins with Nao Takanashi discovering that his sister, whom he has always treated as a sibling, is actually his step-sibling and not biologically related. This revelation complicates their relationship, as Nao begins to see her in a new light, while his sister, who has always harbored romantic feelings for him, becomes more assertive in expressing her emotions.

The narrative explores the dynamics of their relationship, blending elements of romantic comedy with situational humor. Nao struggles to reconcile his newfound awareness of his sister's feelings with his own confusion and societal expectations. Meanwhile, Nao's sister, who is determined to win his affection, employs various tactics to draw his attention, often leading to comedic and awkward situations. The series also introduces other characters, including classmates and friends, who add to the comedic and dramatic tension. These characters often find themselves entangled in misunderstandings and love triangles, further complicating Nao's life.

Throughout the series, the interactions between Nao and his sister are marked by a mix of playful banter, emotional moments, and occasional misunderstandings. The story delves into themes of familial bonds, unrequited love, and the complexities of relationships, all while maintaining a lighthearted and humorous tone. The series balances its comedic elements with moments of introspection, as Nao grapples with his feelings and the evolving nature of his relationship with his sister. The narrative structure is episodic, with each episode presenting new challenges and scenarios that test the characters' relationships and resolve.