"Karakai Jōzu no Takagi-san" centers on the daily interactions between middle school students Nishikata and Takagi. Nishikata, a boy with a competitive streak, often finds himself the target of Takagi's teasing. Takagi, a clever and observant girl, excels at reading Nishikata's reactions and devising playful schemes to fluster him. The series unfolds through a series of lighthearted vignettes, primarily set in their classroom, during school activities, or in their neighborhood.

The dynamic between the two characters is driven by Nishikata's repeated attempts to outsmart Takagi and turn the tables on her teasing. However, his plans frequently backfire due to Takagi's quick thinking and ability to anticipate his moves. Despite his frustration, Nishikata gradually becomes more aware of his growing feelings for Takagi, though he struggles to express them. Takagi, on the other hand, subtly hints at her own affection for Nishikata through her teasing, creating a blend of humor and budding romance.

The narrative is episodic, with each episode featuring self-contained scenarios that highlight the pair's interactions. Common themes include classroom games, challenges, and everyday situations that Takagi uses to tease Nishikata. Supporting characters, such as their classmates Mina, Yukari, and Sanae, occasionally appear, adding variety to the storylines and providing additional comedic moments.

The series maintains a gentle, slice-of-life tone, focusing on the simplicity of middle school life and the innocent, evolving relationship between Nishikata and Takagi. The humor arises from the contrast between Nishikata's earnest attempts to win and Takagi's effortless ability to stay one step ahead, all while subtly exploring the nuances of young love and friendship.