The Crusades. The battles that take place every 200 or so years between the Goddess Athena and Hades, the Lord of the Underworld. In an 18th century European country town, just as the Crusade is dawning, live Tenma and Alone. They have completely different personalities but are the best of friends. One day, Alone meets a woman named Pandora. From that day, the cogs of fate are set into motion.

Golden Saints gather around the Goddess Athena and her Sanctuary, in preparation for the new Crusade against the Underworld warriors. Around this time, as Tenma undergoes training to become a Saintly Warrior, he is reunited with Alone's little sister, Sasha, and learns that she has transformed into Athena. Meanwhile, thinking of his dear and far off friend Tenma, Alone feels lonely and falls into despair.

Tenma and the other Saintly Warriors head towards an Italian town where the warriors of the Underworld are gathered. Tenma realizes it is his hometown, and worries about Tenma's fate. However, Alone appears amongst the burning ruins of the town as the reincarnation of Lord Hades. Tenma shocked by the evil transformation of his dear friend is mercilessly attacked by Alone.

Though she learns of the death of Tenma, and of her brother Alone's reincarnation as Hades, Sasha pushes away her sadness and steadfastly fulfills her role as Athena. Meanwhile, while carrying Tenma's body, the Silver Saint Yato is visited by the Goddess Yuzuriha, who brings him to Jamir. The Chief of Jamir, Hakurei, tells him Tenma is not completely dead.

One of the three strongest Specters, Minos, uses invisible puppet strings to invade the supposedly impenetrable Sanctuary, killing Saints off one after the other. However, a poisonous rose garden appears between Minos and the Sanctuary. Pisces Golden Saint Albafica appears in the middle of the garden. Albafica is immune to the rose's poison, and uses his own blood to kill the Specter Niobe, however...

Albafica fights against Minos with all his might, releasing the "crimson zone." However even that is deflected by the Specter's armor, causing Albafica to finally fall. Minos then heads towards the village outside of the Sanctuary that Albafica was trying to protect. The village is destroyed, and even Agasya, a young girl mourning Albafica, is targeted by Minos.

Tenma and the others hear that the immortal Specters can be destroyed using berries from the Goldenrain tree that grows in the Underworld, so they quickly search for it. They reach the tree, when the Gemini Golden Saint Asmita appears. Is he friend, or foe? Asmita has been studying meditation in his own world, void of light, and so criticizes Tenma's fighting ability, releasing the "Tenmaihourin" which takes away a person's five senses.

Tenma bears the full force of Asmita's attack. When suddenly the Goldenrain reacts to Tenma's rising cosmos and bears fruit. Asmita disappears, and Tenma and the others gather the berries and flee from the Underworld. However, even Jamir feels the evil reach of new Specters. Who should appear before them but Asmita.

The Taurus Golden Saint Aldebaran uses his amazing strength to defeat the Specters as they attempt to close in on the Sanctuary. Then, full of hostility, Heavenly Violent Star Vennu Kagaho comes down, ready to fight. They are equally matched in this breathtaking battle, when Kagaho, affected by Aldebaran's words, binds Aldebaran with his flames and releases a series of major attacks.

Aldebaran bears Kagaho's powerful attack, and defeats him with the "Titan's Nova," a move so powerful it breaks the earth. However, Aldebaran feels Kagaho is not a threat, and does not finish him off. The hurt Kagaho flies away into the twilight sky. Later at the Sanctuary, Athena's protective spell is violently torn by a giant cosmos. Lord Hades appears before Sasha!

Tenma finally returns to the Sanctuary, and challenges Alone to a fight, only to have the tables turned. Then, the Pope arrives and uses an amulet from a previous incarnation of Athena to release the "Talisman Cage" and weaken Hades' power. He tries to seal Hades in the Sanctuary using Athena's cosmos. However, Pandora rushes over...

The painting covering the whole sky, "The Lost Canvas," is said to destroy everyone on earth when completed. Tenma hears to his dismay that the once kind Alone is now trying to destroy all of humanity as Hades. Meanwhile, Pandora desperately realizes that the reincarnation of Hades is incomplete, and sends an assassin to kill Tenma, who is stopping the completion of the reincarnation. The Specters use ultrasonic waves to put Tenma and the others asleep, however...

Tenma leaves the Sanctuary and has resolved to fight on his own. However, on orders from the Pope, he is stopped by the Cancer Golden Saint Manigold and locked in a cell. Back at the Hades palace, so as to fully awaken Hades, who's full reincarnation is prevented by Alone's memories, Hypnos and Thanatos encourage Pandora to trap Hades into an atrium.

Pandora seals away Alone in his studio so that he can focus on the creation of the "Lost Canvas," and completely awakens as the King of Hades. In the shadows, Hades' Councilors Hypnos and Thanatos, worried about the Pegasus Saint and his connections to Hades, begin to take action. At the Pope's orders, the Cancer Saint Manigoldo follows after Tenma. On his way to Hades Castle, Tenma reaches the spot where his old village was destroyed, but in its place he finds a gigantic and sinister forest.

Upon entering the forest of Death, Yuzuriha is separated from the others. She is confronted by her brother, who she thought died years ago. His voice sends her back to the past... Meanwhile, Yato is cornered by a giant centipede. As his consciousness fades, he too remembers his past. Will the two arrive in time to help Tenma in his desperate battle against the Specter Veronica?

Tenma, Yato, and Yuzuriha are surrounded by Veronica's zombies, only to be saved by Cancer Saint Manigoldo. Manigoldo had come to protect Tenma at the pope's orders. With his overwhelming power, he splits Veronica's body in two. But even this isn't enough to kill him, and Veronica tries to cause them all to rot along with the forest. Meanwhile, the Twin Gods Hypnos and Thanatos watch the battle from the palace as they play Chess...

Manigoldo finds the location of the Twin Gods, but is helpless before the might of Thanatos, the God of Death. The Pope Seiji arrives to help him. As he struggles to withstands Thanatos's attacks, Manigold remembers how he met Seiji when he was young. Manigoldo, a war orphan, once thought that human life was valueless... As Thanatos finally reveals his true strength, is there any way for them to win?

Thanatos finally gets serious after being wounded by Manigoldo. But even in the worst position imaginable, Seiji doesn't falter. Don't use the word despair so loosely, he says, and Manigoldo remembers his old days with his master and regains hope. The two use their Sekishiki Meikaiha attack in a final desperate attempt, and succeed in separating Thanatos soul from his body, but...

Hypnos gathers the four gods who control dreams. One of them, the Vision Icelus, appears in Sagittarius, avoiding Capricorn El Cid's attacks, and steals the soul of the unconscious Sisyphus. El Cid leaves the Sanctuary alone to get it back. El Cid, who had always been by Sisyphus side, felt the reason why he wouldn't wake up...

Nearing Hades's castle, Tenma suddenly finds himself standing before his undamaged village. He can't shake the feeling something is wrong as Alone and Sasha tell him everything has been a dream.