Edward and Alphonse Elric live in Resembool with their mother Trisha and father Van Hohenheim, the latter having left without a reason. Trisha soon dies from an illness. After finishing their alchemy training under Izumi Curtis, the Elrics attempt to bring their mother back with alchemy. The transmutation backfires, and Edward loses his left leg while Alphonse loses his body. Edward sacrifices his right arm to retrieve Alphonse's soul, binding it to a suit of armor. Edward is invited by Roy Mustang to become a State Alchemist, to research a way to restore their bodies, and undergoes a painful medical procedure, which grants him prosthetic automail limbs. Edward becomes a State Alchemist, with the title of Fullmetal Alchemist. The Elrics spend the next three years searching for the mythical Philosopher's Stone to achieve their goals.
The Elrics are eventually attacked by an Ishbalan serial killer known as Scar, who targets State Alchemists in revenge for his people's genocide in the Ishbalan civil war. Returning to Resembool to have Edward's limbs repaired by their childhood friend and mechanic, Winry Rockbell, the Elrics meet Dr. Marcoh, who provides them with clues to learn that a Philosopher's Stone is created from human souls. They investigate a laboratory in which the Stones were created, but are hindered by the Homunculi. The Elrics decide to visit Izumi, hoping to improve their alchemy. Mustang's friend Maes Hughes continues the Elrics' research, but is killed by the homunculus Envy.
The Elrics learn from Izumi that she attempted to use alchemy to revive her stillborn child. Alphonse is captured by the homunculus Greed, but is rescued by Amestris' leader King Bradley. Bradley is revealed to be the homunculus Wrath, and brings the captured Greed to the Homunculi's creator, Father. When Greed refuses to rejoin his fellow Homunculi, he is reabsorbed by Father.
After meeting the Xingese prince Lin Yao, who seeks a Philosopher's Stone to cement his position as heir to his country's throne, the Elrics return to Central City, where they learn of Hughes's murder. Lieutenant Maria Ross is framed for Hughes' murder, so Mustang fakes Ross's death and smuggles her out of the country. In encounters with the Homunculi, Mustang kills Lust. Lin captures Gluttony, who swallows Lin, Edward, and Envy into his void-like stomach. They escape from Gluttony's stomach after he takes Alphonse to meet Father, who makes Lin the vessel of Greed. Mustang tries to expose Bradley to the government, but finds that the higher officials are complicit in Father's plans. The Elrics and Mustang are released, but warned not to oppose Father, who seeks to use them as "human sacrifices". Meanwhile, Scar heads north with the Xingese princess May Chang, fired corrupt official Yoki, and kidnapped Dr. Marcoh.