The story is set in 18th century Europe, in a small town in Italy where Tenma, an orphan of Japanese descent, and Alan, a boy who loves painting, are close friends. One day, Alan receives guidance from the priest of the Great Cathedral, Hypnos, to go to a place known as "the earthly paradise" to search for the "true red." There, Alan encounters Pandora, a mysterious girl, and subsequently, Alan's body begins to undergo changes.
Meanwhile, upon the recommendation of the Gold Saint of Libra, Doumu, Tenma decides to go to Greece's Sanctuary to receive Saint training. At the Sanctuary, Tenma reunites with his childhood friend, Sasha, who is also Alan's sister. Sasha, adopted years ago, turns out to be the reincarnation of the goddess Athena.
Two years later, Tenma finally becomes the Saint of the Pegasus constellation. On the other hand, under Pandora's guidance, the soul of Hades awakens within Alan, and he launches a full-scale attack on the Sanctuary...