Soul Eater is set at Death Weapon Meister Academy (死神武器職人専門学校 Shinigami Buki Shokunin Senmon Gakkō?)—"DWMA" (死武専 Shibusen?) for short—located in the fictional Death City[1] in Nevada, United States.[2] The school is run by Shinigami, also known as Death, as a training facility for humans with the ability to transform into weapons, as well as the wielders of those weapons, called meisters (職人 shokunin?).[1] Attending this school are meister Maka Albarn and her scythe partner Soul Eater; ninja Black Star and his partner Tsubaki Nakatsukasa, who can turn into a variety of different weapons such as a kusarigama, shuriken, and ninjatō; and Shinigami's son Death the Kid and his pistol partners Liz and Patty Thompson. The goal of the school's meister students is to have their weapons defeat and absorb the souls of 99 evil humans and one witch, which will dramatically increase the power of the given weapon and turn them into "death scythes", weapons capable of being used by Shinigami.[1]

Shortly after the start of Soul Eater, Maka and Soul Eater face off against the witch Medusa, who forces her child Crona, meister of the demon sword Ragnarok, to collect non-evil human souls and transform into a kishin (鬼神?), an evil demon god. Medusa and her cohorts attack DWMA with the intention of reviving 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. However, Medusa is seemingly killed by the meister and DWMA teacher Franken Stein in the process, while Crona surrenders to the DWMA and goes on to enroll there and befriend Maka.

As a result of Asura's spreading madness, 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 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 in the body of a young girl, and forms a truce with DWMA so they can annihilate the threat of Arachnophobia together. The DWMA students and Medusa's entourage infiltrate Arachnophobia's headquarters where Maka defeats 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's Tables of Contents. Following this, Maka finally succeeds in turning Soul Eater into a death scythe, and the duo become part of the newly formed meister unit Spartoi along with their friends, who rescue Death the Kid and defeat Noah (Greed), though a new Noah (Wrath) is created by the arcane power of the Book of Eibon thanks to its Tables of Contents.