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.

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.

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.

When Ed and Al arrive at the Central Library they discover that it has been burnt to the ground and instead are taken to see Sheska, a former employee who may have the information they seek. Meanwhile, in East City an unexplained explosion causes Colonel Mustang to restart his search for Scar.

Ed and Al sneak inside the Fifth Laboratory to search for more answers about the origins of the Philosopher's Stone. However, it is not long before they are each attacked by former death row murderers who now guard the complex.

When the conspiracy surrounding the Philosopher's Stone closes in on the highest ranks of the military, one of Mustang's most trusted and cherished allies is murdered.

In a violent clash with Greed, King Bradley proves to be a brutal opponent. But the man who finally destroys the Ultimate Shield is more powerful than even the Fuhrer himself.

After learning of Hughes's fate, Ed and Al are ravaged by sadness and guilt. Envy still hides in plain sight among the State Alchemists, and another Homunculus is on the verge of infiltrating their ranks as well.

Freed by an unlikely liberator, Ross's escape is interrupted by Mustang. Even those most loyal to the Flame Alchemist are shaken by the controversial action he takes against the accused killer of Maes Hughes.

Mustang, Alphonse, Havoc, and Hawkeye split up to search a military laboratory. If Lust has her way, none of them will ever see each other alive again.