In Soul Eater, meister (shokunin?) Maka Albarn and her weapon partner Soul Eater are students at the Death Weapon Meister Academy (Shinigami Buki Shokunin Senmon Gakkō?), or DWMA (Shibusen?) for short, located in the fictional Death City, in Nevada, United States. The school has many other students including Black Star with his weapon partner Tsubaki, and Death the Kid with his twin weapon partners Liz and Patti. The school is run by Shinigami, Death himself, as a training facility for weapons and the human wielders of those weapons, the meisters. Maka's goal, along the other meisters, is to have their weapons defeat and absorb the souls of ninety-nine evil humans and one witch, which will dramatically increase the power of the given weapon and thus be capable of being used by shinigami; these weapons are called Death Scythes. In the universe of Soul Eater, witches are powerful beings and the natural enemies of DWMA, as almost all of them have a destructive nature and almost all desire anarchy and chaos.
At the start of Soul Eater, Maka and Soul encounter the meister Crona and Crona's weapon Ragnarok; Crona is being forced to attack non-evil humans by Crona's mother and witch Medusa. Medusa eventually recruits the witches Eruka and Mizune, along with the immortal werewolf Free. Medusa and her cohorts attack DWMA on the eve of the festival to commemorate the establishment of DWMA. Medusa's goal is to revive the first "kishin", an evil demon god that nearly destroyed everything by plunging the world into madness, named Asura who was sealed beneath the DWMA by Shinigami. Medusa's group successfully revives Asura, though Medusa is seemingly killed in the process.
As Asura escapes the DWMA, the world is plunged into chaos and insanity, and because of this, Medusa's older sister Arachne comes out of hiding after 800 years. Arachne reforms her organization Arachnophobia, which poses itself as a serious threat to the DWMA; Arachne is joined closely by her demon butler Mosquito and demon weapon Giriko. The DWMA calls in the Death Scythes Justin Law, Yumi Azusa, and Marie Mjölnir to aide in the fight against Arachnophobia. During this time, Medusa is proven to be alive and possesses a young girl named Rachel. Maka and the other students are progressively getting stronger as they train and participate in various battles. Medusa makes a truce with the DWMA for a time so together they can annihilate the threat of Arachnophobia. Once Arachne is killed by Maka, Medusa betrays the DWMA and takes possession of Arachne's previously discarded body, regaining her lost strength.
The anime series deviates from the manga considerably after episode thirty-five. After giving the DWMA information on Arachnophobia, Medusa takes advantage of Stein's increasing madness to lure him away with her. Crona and Marie decide to search for Medusa and bring back Stein. Medusa is defeated by Maka's demon hunter attack after Crona is nearly killed. Stein goes back to the DWMA having overcome the madness within himself. Shinigami and Asura resume their fight, which results in Shinigami's defeat when Asura threatens Kid's life. Asura eats Arachne's soul, and is confronted by Kid, Black Star and Maka. In the final battle, Maka defeats Asura and the world returns to normal.