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.

Despite having a good reputation as one of the most seasoned guards in the local guild of Mebuki, Kikuru Madan believes he has been wasting his youth and hopes to spend the rest of it like any other person. However, his conscience prevents him from retiring at present, as he worries about the guild's future without him. Coincidentally—as if to help him find his successor—the guild's receptionist, Enome, assigns Kikuru four fresh recruits: the energetic beastwoman Hitamu Hitamuki Kyan, the prodigy Maidena Ange, the laid-back Toxico Dannar, and the stalwart Hanabata Nohkins. Although each of them possesses significant talents, they also display characteristics that detract from their potential—including Hitamu's extreme clumsiness and Hanabata's unintentional perverseness. As if there was not enough to deal with, the monsters outside Mebuki's walls start exhibiting odd behavior by targeting women salaciously, causing the party endless problems in more ways than one. Nevertheless, Kikuru is committed to retiring early; to achieve his goal, the guidance he gives the trainees will be absolutely essential.

Within one's Book of Fate is their destiny. Written by the mysterious Story Tellers, these books decide every small detail of one's life. Some Story Tellers, however, choose to interfere with the stories of others rather than write their own. These malevolent beings are known as Chaos Tellers, who seek to ruin stories by overwriting the Books of Fate. Ex, Reina, Tao, and Shane were born with blank books. Ostracized by society due to this abnormality, they abandon their respective stories in search of better lives. In the vast unknown, they encounter famous fairy tale characters such as Cinderella, Momotarou, and Snow White. All the while, they work to subdue the Chaos Tellers and return peace and order to the stories.