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, 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, and Pisces Golden Saint Albafica appears. 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 learn the immortal Specters can be destroyed using berries from the Goldenrain tree that grows in the Underworld. When they reach the tree, the Gemini Golden Saint Asmita appears. 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.

Pandora seals away Alone in his studio so that he can focus on the creation of the Lost Canvas, and completely awaken as Hades. In the shadows, Hades's councillors 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's Cathedral, 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 the Dead, Yuzuriha is separated from the others. She is confronted by her brother Tokusa, 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, and thinks about his reason to fight. Will the two arrive in time to help Tenma in his desperate battle against the dreadful Specter Veronica?

Tenma, Yato, and Yuzuriha are surrounded by Veronica's zombies, only to be saved by the 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 the Specter, and Veronica tries to cause them all to rot along with the forest. Meanwhile, the twin gods Hypnos and Thanatos watch the battle from their palace as they play chess…

Cancer Manigoldo finds the location of the twin gods, but is helpless before the might of Thanatos, the god of death. Pope Sage arrives to help his disciple. As he struggles to withstand Thanatos's attacks, Manigoldo remembers how he met Sage when he was young... the Cancer Saint, a war orphan, once thought that human life was valueless... as Thanatos finally reveals his true strength and unleashes his divine wrath, is there any way for master and pupil to win?

Thanatos finally gets serious after being wounded by Manigoldo. But even in the worst position imaginable, Sage doesn't falter. "Don't use the word despair so loosely", he says, and Manigoldo remembers his old days with his master and the desperation he felt when he saw the destiny of humans after death, regaining hope and determination to fight. The two use their Sekishiki Meikai Ha attack in a desperate attempt, and end up succeeding in separating Thanatos's soul from his physical body, but that isn't enough to defeat the god of death...

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

Nearing Hades's Cathedral, Tenma suddenly finds himself standing before his village, seemingly undamaged. He can't shake the feeling something is wrong as Alone and Sasha – who appear as their children selves – tell him everything up until now has been a dream... the truth, however, is the other way round. Carrying out Hypnos's orders, the dream gods trapped Tenma, Yato, Yuzuriha and Sisyphos in dream prisons, deep inside their realm – the Dream World.

With one of the four gods down, El Cid finds himself confronted by Icelus. The beastly god continues to overpower El Cid with his dimensional abilities, but the Capricorn Saint is determined to rescue Sisyphos. Meanwhile, Tenma fights his way out of his dream prison and faces against Morpheus.

Tenma and El Cid are helpless before the combined might of Oneiros and his fellow Dream Gods: Phantasos, Icelos and Morpheus. But Athena appears in the Dream World in order to save Sisyphos; Tenma and El Cid begin the fight anew to protect Athena, and succeed in removing Oneiros from the Dream World, taking the fight into the real world.

With the four Dream Gods finally vanquished, Hypnos's divine barrier is lifted, and Athena's forces are free to march forward into Hades's Cathedral! Hakurei gives them a rousing speech posing as Sage, then enters the Cathedral alone to fulfill his deep-seated vengeance against Hypnos, who killed his comrades in the previous Holy War. Meanwhile, as Alone paints the Lost Canvas in the depths of the Dream World, Hypnos plays with his mind in order to turn him into the real King Hades.

With the four Dream Gods finally vanquished, Hypnos's divine barrier is lifted, and Athena's forces are free to march forward into Hades's Cathedral! Hakurei gives them a rousing speech posing as Sage, then enters the Cathedral alone to fulfill his deep-seated vengeance against Hypnos, who killed his comrades in the previous Holy War. Meanwhile, as Alone paints the Lost Canvas in the depths of the Dream World, Hypnos plays with his mind in order to turn him into the real King Hades.

Hakurei ventures into the Cathedral alone, protected by a blade blessed by the previous incarnation of Athena. He tears apart the opposing Specters until he reaches the center of Hades's dark barrier that permeates the castle and hinders the Saints. When he attempts to destroy it with his sword, Hypnos appears, revealing to have intercepted and defeated Hakurei's pupils Shion and Yuzuriha. Will Hakurei be able to take down the foe he has hated since the last Holy War?

Hakurei finally defeats Hypnos by using his most powerful technique with the help from his former fellow saints from the last Holy War, but he's murdered by Hades just as he was about to destroy the dark barrier. Shion, enraged, attacks Hades causing him no harm. Amidst all this debacle, Dohko, Tenma and Yato arrive to join Shion and Yuzuriha. The Pegasus Saint fights Hades, but the King of the Underworld overpowers him. In the verge of an inminent death, Tenma is saved by Dohko by using all his cosmos.