"Fullmetal Alchemist: The Sacred Star of Milos" is a standalone film set within the "Fullmetal Alchemist: Brotherhood" universe, focusing on Edward and Alphonse Elric as they become entangled in a conflict in the remote valley of Table City. The story begins with the Elric brothers pursuing a fugitive alchemist, Melvin Voyager, who escapes into the underground slums of Milos, a region oppressed by the neighboring countries of Creta and Amestris. The Milosians, led by a young woman named Julia Crichton, are fighting for independence and the restoration of their sacred star, a symbol of their heritage and freedom.

Julia seeks to reclaim the sacred star, a powerful alchemical artifact, from the clutches of Creta and Amestris, who exploit the valley for its resources. The Elric brothers are drawn into the conflict when they discover that the sacred star is tied to a mysterious alchemical power capable of reshaping the land. As they delve deeper, they uncover the tragic history of Milos, including the betrayal and death of Julia's brother, Ashley, who was manipulated by Melvin Voyager in a failed attempt to harness the star's power.

The narrative explores themes of oppression, resistance, and the consequences of wielding alchemy for personal gain. Edward and Alphonse must navigate the moral complexities of the conflict, balancing their desire to help the Milosians with their commitment to the principles of alchemy. The film culminates in a climactic battle as Julia and the Milosians rise against their oppressors, with the Elric brothers playing a pivotal role in ensuring the sacred star is used to liberate rather than destroy.

Key characters include Edward and Alphonse Elric, whose bond and alchemical expertise drive the story; Julia Crichton, a determined leader fighting for her people's freedom; Melvin Voyager, a morally ambiguous alchemist with his own agenda; and Lieutenant Colonel Roy Mustang, who provides support from the Amestris military. The film expands on the world-building of the "Fullmetal Alchemist" series while maintaining a self-contained narrative that explores the ethical dilemmas and human cost of alchemy.