After escaping from Central Prison, the Freezing Alchemist, Isaac McDougal, sets his plan in motion to kill Führer King Bradley. However, under the command of Lt. Col. Roy Mustang, the military and State Alchemists attempt to stop him.

On the way to Lior, Ed and Al reminisce about the events that lead to them being trapped in their current bodies by breaking the taboo of human transmutation. Meanwhile, Colonel Mustang looks back on the first time he met the Elric brothers.

Ed and Al arrive at the city of Lior, hoping to find the legendary Philosopher's Stone so they can return their bodies back to normal. There, they meet a priest named Cornello, who is able to perform "miracles." As Ed and Al investigate, they find out the truth about Cornello.

Ed and Al become interested in biological transmutation after witnessing a chimera in Lior, so Colonel Mustang introduces them to an expert in the field, Shou Tucker, the Life-binding Alchemist. Meanwhile, a serial killer whose targets are only State Alchemists is on the loose in Central.

After learning about what happened to Shou Tucker and his daughter Nina, the Elric brothers begin to question what alchemy really is. Meanwhile, Colonel Mustang and the other State Alchemists track down the serial killer Scar.

After their encounter with Scar, Ed's automail and Al's armor need to be repaired, so Major Armstrong escorts them to their hometown of Risembool. On their way there, they spot Dr. Marcoh, a scientist who helped create the Philosopher's Stone, and try to convince him to give them the location of the Stone's research data.