Maka and Soul battle the witch Medusa, who forces Crona, her child and meister of the demon sword Ragnarok, to collect non-evil human souls and eventually transform into a kishin (鬼神), an evil god. Medusa and her cohorts attack DWMA to revive Asura, the first kishin who nearly plunged the entire world into madness before being sealed beneath DWMA by Shinigami. Despite the combined efforts of Maka, Black Star, and Death the Kid, Medusa's group successfully revives Asura, who leaves to spread chaos around the world after a brief battle with Shinigami. Medusa is seemingly killed by meister and DWMA teacher Franken Stein, while Crona surrenders to DWMA and enrolls there.

As a result of Asura's spreading madness, Medusa's sister Arachne comes out of hiding and reforms her organization, Arachnophobia, which poses a serious threat to DWMA. Shinigami calls in death scythes from around the world to aid in the fight against Arachnophobia. During this time, Medusa reappears with her soul possessing the body of a young girl, and forms a truce with DWMA so they can annihilate Arachnophobia together. The DWMA students and Medusa's entourage infiltrate Arachnophobia's headquarters, where Maka kills Arachne, only for Medusa to betray DWMA, possess Arachne's body, and brainwash Crona into rejoining her. Meanwhile, Death the Kid is captured by Noah, an artificial construct created from the Book of Eibon. Following this, Maka uses Arachne's soul to turn Soul into a death scythe. The duo become part of the newly formed meister unit Spartoi along with their friends, who rescue Death the Kid and defeat Noah.

Crona resurfaces in a city in Russia, destroying it and the death scythe stationed there, before being provoked by Medusa into killing her and getting taken by insanity. Maka is ordered by Shinigami to hunt down Crona; while searching for Crona with her powers, she unwittingly detects Asura's location on the cartoonish moon within the atmosphere. DWMA launches an attack on the moon to defeat Asura, aided by the witches after Death the Kid convinces them to establish a temporary alliance. During the battle, Crona absorbs Asura's body before being overtaken by him. Maka, Black Star, and Death the Kid eventually restore Crona's sanity and defeat Asura by sealing him on the moon with his own blood; Crona willingly remains with Asura to keep him imprisoned, and Maka promises to one day rescue Crona. The DWMA forces return to Earth, where Death the Kid becomes the new Shinigami following his father's death, and establishes a peace treaty with the witches.