"Rokudō no Onna-tachi" centers around Tōsuke Rokudō, a high school student who inherits a cursed power known as the "Rokudō Curse" from his ancestor, Rokudō Chūan. This curse causes women around him to become irrationally infatuated with him, often leading to chaotic and comedic situations. Despite the seemingly advantageous nature of the curse, it brings more trouble than benefit, as the women affected by it exhibit extreme and often dangerous behavior in their pursuit of him.

The story begins with Tōsuke struggling to live a normal life while dealing with the unintended consequences of the curse. His childhood friend, Ranna Himawari, is one of the few unaffected by the curse, providing a rare sense of stability in his life. However, as the narrative progresses, Tōsuke encounters various women who fall under the curse's influence, including delinquents, rivals, and even supernatural entities. Each character brings their own unique challenges, further complicating Tōsuke's attempts to maintain control over his life.

A key figure in the series is Yūka Hanazono, a delinquent girl who becomes one of the first victims of the curse. Her aggressive and possessive behavior sets the tone for the chaotic relationships that follow. Another significant character is Reiko Tamura, a teacher who also succumbs to the curse, blurring the lines between professional and personal boundaries. The curse's effects are not limited to humans, as Tōsuke later encounters a yokai named Chiyo, who becomes infatuated with him, adding a supernatural layer to the story.

As the series unfolds, Tōsuke learns more about the origins of the curse and its connection to his ancestor, Rokudō Chūan. The curse is revealed to be a double-edged sword, as it not only attracts women but also amplifies their negative traits, leading to increasingly volatile situations. Tōsuke's journey involves navigating these challenges while seeking a way to break the curse and regain control over his life.

The narrative balances comedic elements with moments of tension and drama, as Tōsuke's relationships with the affected women evolve. The series explores themes of fate, free will, and the complexities of human emotions, all while maintaining a lighthearted tone through its exaggerated and often absurd scenarios. The interactions between Tōsuke and the various women drive the plot forward, creating a dynamic and engaging story that blends humor, romance, and supernatural elements.