Des de temps mitològics, té lloc una guerra santa en què la deessa Atenea i Hades s'enfronten cada dos-cents anys pel destí de la Terra. En Tenma, l'Alone i la Sasha, tres orfes que han crescut junts, s'acomiaden amb la promesa de tornar a reunir-se algun dia. Però els seus destins fan un gir inesperat que acaba unint-los tràgicament. Mentre l'impulsiu Tenma s'entrena per convertir-se en cavaller d'Atenea, el dolç i bondadós Alone descobreix que està destinat a convertir-se en la personificació d'Hades en aquesta era. És aleshores quan l'Alone comença la creació d'una pintura sense precedents, el quadre perdut, amb el qual vol portar la salvació al món. Quan la pintura cobreixi el cel, el món arribarà a la seva fi.

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.

Seguint les ordres del Santuari, un esquadró de combat format per Cavallers de Plata va a prendre contacte amb l'enemic. Algunes de les seves habilitats són equiparables a les dels Cavallers d'Or.

Una dona desconeguda apareix per emportar-se el cos del Pegàs i tornar-lo a la vida. L'Unicorn els acompanya a un regne misteriós.

En Minos, un dels tres jutges, arriba amb els seus sequaços a les portes del santuari de Peixos. L'Alfabica surt en defensa del temple per enfrontar-se a en Minos i el seu temible poder que converteix qualsevol enemic en un titella.

Continua la lluita a mort de l'Albafica de Peixos i en Minos. Després d'una intensa lluita, el cavaller daurat cau vençut aparentment i en Minos s'encaminarà a destruir la vida del poble del Santuari d'Atenea fins que apareix en Shion d'Aries per aturar-lo. Quan sembla tot perdut, torna a aparèixer l'Albafica que sacrificarà tot el seu poder còsmic de les roses per aconseguir vèncer el poderós Minos.

L'esperit d'en Tenma, en Yato i la Yuzuriha aniran a la recerca dels fruits del Sapinda i en el seu camí es trobaran amb el ca Cèrber i l'Hades. Prop del seu objectiu, en Yato i la Yuzuriha seran paralitzats per l'enigmàtic cavaller daurat Asmita de Verge. En Tenma s'haurà d'enfrontar amb aquest cavaller, que tindrà la mateixa força còsmica de Buda.

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!

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.

En Tenma, sentint-se culpable de la mort d'Aldebaran de Taure, decideix marxar del Santuari per evitar més vessament de sang però serà empresonat per Manigold de Càncer. Mentrestant, al castell d'Hades, la Pandora perdrà el seu control com també la seva confiança en benefici dels déus bessons Hypnos i Thanatos, que vetllaran perquè Hades enllesteixi el Quadre Perdut. Finalment, en Tenma, en Yato i la Yuzuriha es dirigiran cap al castell d'Hades.

En Tenma, en Yato i la Yuzuriha es dirigeixen cap al castell d'Hades, a Itàlia. En el seu camí es trobaran un bosc misteriós on seran atacats per una bandada d'ocells. Això farà separar el grup i en Tenma es retrobarà amb els seus antics amics de l'orfenat que creia morts.

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.