"Otaku no Musume-san" centers on Kanau, a young girl who unexpectedly reconnects with her estranged father, Kouhei, after years of separation. Kouhei is a self-proclaimed otaku, deeply immersed in anime, manga, and gaming culture, living a reclusive lifestyle. Kanau, on the other hand, is a pragmatic and independent middle school student who initially struggles to understand her father's eccentricities. The narrative explores their evolving relationship as they navigate the challenges of living together, bridging the gap between their vastly different personalities and lifestyles.

The story delves into themes of family, acceptance, and personal growth. Kanau gradually learns to appreciate her father's passions, while Kouhei begins to take on more responsibility as a parent, striving to provide stability and support for his daughter. Their interactions are often humorous and heartwarming, highlighting the complexities of their bond. Secondary characters, such as Kanau's classmates and Kouhei's otaku friends, add depth to the narrative, offering perspectives on friendship, societal expectations, and the otaku subculture.

As the series progresses, Kanau and Kouhei face various challenges, including misunderstandings, societal judgment, and personal insecurities. These obstacles test their relationship but ultimately strengthen their connection. The manga balances comedic moments with poignant reflections on family dynamics, creating a narrative that resonates with readers through its relatable and heartfelt portrayal of a father and daughter learning to understand and support each other.