"Boys Over Flowers" centers on Tsukushi Makino, a working-class girl who attends the prestigious Eitoku Academy, a school dominated by wealthy and elite students. The story begins when Tsukushi stands up to the F4, a group of four powerful and influential boys—Tsukasa Domyoji, Rui Hanazawa, Sojiro Nishikado, and Akira Mimasaka—who rule the school through intimidation and fear. After her defiance, Tsukushi becomes a target of bullying orchestrated by the F4, particularly Domyoji, the group's volatile leader. Despite the hostility, Tsukushi's resilience and determination earn her the respect of some students and gradually draw the attention of the F4 members.

As the narrative progresses, Tsukushi's relationship with the F4 becomes increasingly complex. Rui, the quiet and introspective member of the group, develops a close bond with Tsukushi, though his feelings remain ambiguous. Domyoji, initially her primary antagonist, begins to show a softer side and eventually falls in love with her. Their relationship becomes the focal point of the story, marked by Domyoji's intense emotions and Tsukushi's struggle to reconcile her feelings for him with her disdain for his arrogance and privilege. The dynamic is further complicated by external pressures, including Domyoji's overbearing mother, who disapproves of Tsukushi's lower social status and attempts to sabotage their relationship.

Throughout the series, Tsukushi navigates the challenges of her social standing, her evolving relationships with the F4, and her own personal growth. The story explores themes of class disparity, loyalty, and self-discovery, as Tsukushi's journey intertwines with the lives of the F4 members, each of whom faces their own struggles and insecurities. Rui grapples with unrequited love and his quiet longing for Tsukushi, while Sojiro and Akira provide comic relief and occasional moral support. Domyoji's character arc is particularly significant, as he transforms from a spoiled, entitled bully into a more mature and empathetic individual, largely due to Tsukushi's influence.

The narrative spans a variety of settings, from the halls of Eitoku Academy to international locations, as the characters confront family drama, romantic rivalries, and personal crises. The series balances dramatic moments with lighthearted humor, creating a compelling mix of romance, comedy, and drama. Tsukushi's unwavering determination and moral integrity serve as a counterpoint to the opulence and corruption surrounding her, making her a relatable and inspiring protagonist. The interactions between the characters drive the plot forward, culminating in a resolution that addresses their individual growth and the bonds they have formed.