Edward Elric, a young, brilliant alchemist, has lost much in his twelve-year life: when he and his brother Alphonse try to resurrect their dead mother through the forbidden act of human transmutation, Edward loses his brother as well as two of his limbs. With his supreme alchemy skills, Edward binds Alphonse's soul to a large suit of armor. A year later, Edward, now promoted to the fullmetal alchemist of the state, embarks on a journey with his younger brother to obtain the Philosopher's Stone. The fabled mythical object is rumored to be capable of amplifying an alchemist's abilities by leaps and bounds, thus allowing them to override the fundamental law of alchemy: to gain something, an alchemist must sacrifice something of equal value. Edward hopes to draw into the military's resources to find the fabled stone and restore his and Alphonse's bodies to normal. However, the Elric brothers soon discover that there is more to the legendary stone than meets the eye, as they are led to the epicenter of a far darker battle than they could have ever imagined.

In desperation, Edward Elric sacrificed his body and soul to rescue his brother Alphonse, and is now displaced in the heart of Munich, Germany. He struggles to adapt to a world completely foreign to him in the wake of the economic crisis that followed the end of World War I. Isolated and unable to return home with his alchemy skills, Edward continues to research other methods of escaping the prison alongside colleagues who bear striking resemblances to many of the people he left behind. As dissent brews among the German citizenry, its neighbors also feel the unrest of the humiliated nation. Meanwhile, Alphonse continues to investigate Edward's disappearance, delving into the science of alchemy in the hopes of finally reuniting with his older brother.

After a horrific alchemy experiment goes wrong in the Elric household, brothers Edward and Alphonse are left in a catastrophic new reality. Ignoring the alchemical principle banning human transmutation, the boys attempted to bring their recently deceased mother back to life. Instead, they suffered brutal personal loss: Alphonse's body disintegrated while Edward lost a leg and then sacrificed an arm to keep Alphonse's soul in the physical realm by binding it to a hulking suit of armor. The brothers are rescued by their neighbor Pinako Rockbell and her granddaughter Winry. Known as a bio-mechanical engineering prodigy, Winry creates prosthetic limbs for Edward by utilizing automail, a tough, versatile metal used in robots and combat armor. After years of training, the Elric brothers set off on a quest to restore their bodies by locating the Philosopher's Stone—a powerful gem that allows an alchemist to defy the traditional laws of Equivalent Exchange. As Edward becomes an infamous alchemist and gains the nickname Fullmetal, the boys' journey embroils them in a growing conspiracy that threatens the fate of the world.

Chasing a runaway alchemist with strange powers, brothers Edward and Alphonse Elric stumble into the squalid valley of the Milos. The Milosians are an oppressed group that seek to reclaim their holy land from Creta: a militaristic country that forcefully annexed their nation. In the eye of the political storm is a girl named Julia Crichton, who emphatically wishes for the Milos to regain their strength and return to being a nation of peace. Befriending the girl, Edward and Alphonse find themselves in the midst of a rising resistance that involves the use of the very object they have been seeking all along—the Philosopher's Stone. However, their past experiences with the stone cause them reservation, and the brothers are unwilling to help. But as they discover the secrets behind Creta's intentions and questionable history, the brothers are drawn into the battle between the rebellious Milos, who desire their liberty, and the Cretan military, who seek absolute power.