Edward and Alphonse Elric began the way most tragic stories do: with a desperate act they could never undo. Their attempt to resurrect their mother through human transmutation failed catastrophically — Alphonse lost his body, Edward lost his arm and his leg. Seeking the Philosopher's Stone as a means to restore what was taken, the brothers expose the false prophet Cornello and prove his stone is a fake, then head back to Central by train — which is promptly hijacked by a militant group threatening hostages. The Elrics resolve it and free the prisoner, a girl named Corniche Royce who can perform healing alchemy and is headed to the State Alchemy Examination. She joins them.
In Central, Corniche finds she left her exam essay behind. King Bradley appears and offers a compromise: defeat Major Alex Louis Armstrong and earn certification on the spot. She fails. Edward receives orders for a chimera extermination mission in East City and authorization to form a Special Squad. After considerable resistance, he recruits Colonel Roy Mustang and Major Armstrong. En route the train is hijacked again — by the real militant group this time — the party handles it, and the investigation into chimera activity begins in earnest.
The trail leads through a town where two imposters calling themselves the Elric brothers are causing trouble. They are tracked down and revealed to be alchemist-created manikins, built by a sixteen-year-old girl named Cate Rham, who escapes. An eccentric alchemist named Dalt Daimler is identified as a chimera suspect — he flees before capture and turns up dead near the brothers' hometown of Resembool, missing a bag he was carrying.
The bag surfaces when a criminal named Randy the robber is identified as the killer. He is captured and interrogated, but a masked alchemist called Lincor arrives with Cate to intercept — seizing the bag and unleashing a devastating attack that buys them time to escape. Edward suspects the bag contains a Philosopher's Stone.
Mustang and State Alchemist Lieutenant Colonel Aston Martins — the Thunder Alchemist — notice that Lincor resembles the supposedly dead State Alchemist Colonel Seraphy Royce, the Tuning Alchemist, who was reported killed in the Ishval War. Corniche's surname is also Royce. Lincor is tracked to a hideout in the East City sewers — Cate, Randy, and a scarred man are present, but Lincor himself is not. While the party is en route back, chimeras assault the East Headquarters, which the squad clears.
A final lead takes the party to a castle in the southeast. Lust, Cate, and Randy are each defeated again. Lincor releases a giant regenerating chimera from Dalt's bag; Lieutenant Colonel Martins sacrifices himself to protect the party. Edward confronts Lincor over the cost — something precious paid in exchange for a power supposedly used to protect others. Corniche presses her possible brother to remember what he once believed. Lincor denies knowing her, attacks, and is defeated. In a last act, he merges with the castle itself. Corniche uses her full power to heal the party, and they prevail. In his final moments, Lincor's memory of his mother returns. He traded his memory of his sister for the power he believed would protect people, and he dies at peace.
Corniche retakes the State Alchemy exam and earns the title of Tuning Alchemist in her brother's name. She accepts it and departs to make amends for the harm he caused.