A rural gynecologist named Gorou Amamiya has spent years supporting the idol Ai Hoshino, the luminous center of the pop group B-Komachi. His life takes an impossible turn when Ai secretly appears at his clinic, pregnant with twins. Sworn to protect her secret, Gorou is murdered by a mysterious stalker on the night she gives birth. In his final moment, he reincarnates as Aquamarine Hoshino, Ai's newborn son, retaining all memories of his past life. Unbeknownst to him, his twin sister Ruby is the reincarnation of Sarina Tendouji, a terminally ill former patient of Gorou's who also adored Ai.

The twins grow up under Ai's care, witnessing her navigate the brutal demands of the entertainment industry while hiding her motherhood. When the children are four years old, the same stalker who killed Gorou finds Ai and fatally stabs her. As Ai dies in their arms, Aqua pieces together a clue suggesting their unknown father orchestrated the murder. Consumed by a thirst for revenge, he vows to enter the entertainment world, climb its ranks, and make his father pay.

The story then leaps forward to the twins teenage years in Tokyo. Aqua enrolls in a performing arts high school, using his past-life maturity and cunning to secure work as an actor. His goal is to infiltrate the industry's upper echelons to access the information needed to identify and destroy his father. Ruby follows a different path, determined to fulfill their mother's legacy by becoming an idol herself. She forms a new version of B-Komachi alongside a sharp-tongued former child actress named Kana Arima and a charismatic older YouTuber known as Mem-cho.

As Aqua and Ruby chase fame, the series explores the often harsh realities of show business, from the pressures of reality dating shows and the complexities of 2.5-dimensional stage plays to the viciousness of social media and the manipulative power of talent agencies. Aqua uses a relationship with the talented actress Akane Kurokawa as part of his investigation, while Ruby discovers the horrifying truth about her brother's secret mission. Their separate quests for the truth and justice for their mother build toward a climactic confrontation with the forces that destroyed their family, concluding in a feature film titled Oshi no Ko: The Final Act.