"Nazo no Kanojo X" centers on the unconventional relationship between Tsubaki Akira, a high school student, and Mikoto Urabe, a mysterious transfer student. The story begins when Tsubaki becomes intrigued by Urabe's aloof demeanor and peculiar habits, such as carrying scissors and sleeping during class. Their connection deepens when Tsubaki falls ill, and Urabe offers him a unique remedy: drinking her saliva. This act, which Urabe refers to as a way to "share dreams," forms the foundation of their bond, as Tsubaki begins to experience Urabe's memories and emotions through her saliva.

As their relationship progresses, Tsubaki and Urabe navigate the complexities of adolescence, exploring themes of intimacy, trust, and communication. Urabe's enigmatic nature and her reluctance to conform to societal norms create tension and curiosity, while Tsubaki's growing affection for her leads him to question his own feelings and desires. The series delves into their evolving dynamic, highlighting the challenges of understanding and accepting one another in a relationship that defies conventional norms.

Supporting characters, such as Tsubaki's childhood friend Oka Ayuko and classmate Keiichi Kojima, add layers to the narrative, providing contrasting perspectives on love and relationships. Ayuko's unrequited feelings for Tsubaki and Kojima's playful yet insightful observations contribute to the exploration of human emotions and social dynamics. The series balances its focus on the central relationship with moments of humor, introspection, and occasional surrealism, creating a unique blend of romance and psychological exploration.

Throughout the story, the act of sharing saliva serves as a metaphor for emotional vulnerability and connection, emphasizing the importance of mutual understanding in relationships. The narrative remains grounded in the everyday experiences of high school life while incorporating elements of mystery and fantasy, resulting in a distinctive portrayal of young love and self-discovery.