The story focuses on an orphan named Seiya who was forced to go to the Sanctuary in Greece to obtain one of the "Cloths" (聖衣クロス, Kurosu), the Bronze Cloth of the Pegasus constellation, a protective armor worn by the Greek goddess Athena's 88 warriors known as "Saints" (聖闘士セイント, Seinto, or "Knights" in some adaptations). Upon awakening his "Cosmo" (小宇宙コスモ, Kosumo), the power of the Saints which is an inner spiritual essence originated in the Big Bang, Seiya quickly becomes the Pegasus Saint and returns to Japan to find his older sister.
Because his sister disappeared the same day Seiya went to the Sanctuary, Saori Kido, the granddaughter of Mitsumasa Kido (the person who sent all the orphans to train) makes a deal with him to go to fight in a tournament called the Galaxian Wars. In this tournament, all the orphans who survived and became Bronze Saints must fight to win the most powerful Cloth: The Sagittarius Gold Cloth. If Seiya goes to compete there and wins, Saori would start a search to find Seiya's sister. The tournament is interrupted by the revengeful Phoenix Bronze Saint, Ikki, who wishes to eliminate track from the people who forced him to undergo his training. He steals parts from the Sagittarius Cloth and eventually fights against the remaining Bronze Saints: Seiya, Shun (Ikki's brother), Shiryū, and Hyōga.
Upon Ikki's defeat, the Bronze Saints are attacked by the Silver Saints sent by the Sanctuary's Pope to eliminate them. When they remain victorious, the Bronze Saints learn that Saori is Athena's reincarnation and that the Pope once tried to kill her as a baby. The Sagittarius Gold Saint Aiolos saved Saori but was killed shortly afterwards and gave Saori to her adopted grandfather, Mitsumasa Kido. Deciding to join forces with Saori, the Bronze Saints go to the Sanctuary to defeat the Pope, but upon their arrival, Saori is severely wounded by a gold arrow from a Silver Saint. Believing the Pope may be able to heal her, the Bronze Saints go to find him. To do so, they have to go through 12 temples, each one guarded by one Gold Saint (the most powerful Saints of Athena). Following several battles, Seiya gets to the Pope's temple and learns that he is the Gold Saint Gemini Saga, who in his madness killed the real Pope to obtain more power. With help from his friends' Cosmos, Seiya is able to knock out Saga and use the shield from Athena's statue to heal Saori. Shortly afterwards, Saga, having come to his senses, commits suicide as a self-punishment.
In the second story arc, the Greek god Poseidon reincarnates within the body of Julian Solo, the heir to a rich and powerful family, who follows his will of flooding the Earth. Saori goes to his Temple, where Julian offers her to reduce the flooding by absorbing the water inside the Oceans' Central Pillar. Following Saori, Seiya, Hyōga, Shun and Shiryū go to Poseidon's underwater Temple and are confronted by his underlings, the Marines. As Seiya, Hyōga, and Shiryū make their way to Julian, Ikki learns that the mastermind behind this war is Saga's twin, Gemini Kanon, who is manipulating Poseidon. During the final battle, Poseidon's spirit awakes within Julian and manages to defeat his opponents. Saved by the Saints from the Pillar, Saori seals Poseidon's soul within her amphora.
The third and last arc follows how Hades, the Underworld god, is freed from his seal and revives the deceased Gold Saints and the Pope Aries Shion, and alongside some of his 108 Specters, sends them to the Sanctuary to kill Athena. The remaining Gold Saints serving Athena are able to subdue the enemies, but Saori then commits suicide. This act is instead meant to directly send her to the Underworld to face Hades, and the Bronze Saints follow her. Shion reveals that the revived Gold Saints' true intentions were of giving Saori her own Cloth, and gives it to Seiya's group before dying once again. In the Underworld, as the Saints fight Hades' Specters, Shun is possessed by Hades. Saori reaches Hades and expels his soul from Shun's body. Hades then takes Saori to Elysium, and the five Bronze Saints follow them. In the final fight against Hades and his two followers, Hypnos and Thanatos, the Saints gain the strongest God Cloths and use them to aid Saori in defeating Hades. However, Seiya also sacrifices himself by receiving one of Hades' attacks, and the Saints return to Earth with his body.