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Plot

The game takes place in Sanctuary, the dark fantasy world of the Diablo series, twenty years after the events of Diablo II. Deckard Cain and his niece Leah are in Tristram Cathedral investigating ancient texts regarding an ominous prophecy. A mysterious star falling from the sky strikes the Cathedral, creating a deep crater into which Deckard Cain disappears.

The protagonist arrives in the town of New Tristram to investigate the falling star which struck the cathedral, which is now emanating risen dead; the same cathedral that was the setting of Diablo. The protagonist accompanies Leah to the cathedral in order to rescue Cain from the crater into which he fell. After rescuing Cain, the protagonist learns that the only way to the fallen star is to defeat King Leoric, the former ruler of Tristram known now as the Skeleton King. Cain informs the protagonist that Leoric's crown must be recovered to defeat him, and the protagonist searches for Leoric's crown with the aid of Haedrig Eamon, the blacksmith of New Tristram. After recovering the crown, the protagonist defeats Leoric and finds a stranger where the fallen star landed. The stranger's only memory is of a sword that shattered into three pieces as he fell.
The hero recovers the sword pieces from the Khazra Den and the Drowned Temple, opposed by the witch Maghda, leader of the local cult known as the Dark Coven. Maghda, however, recovers the third piece before the protagonist does and attempts to force Cain to repair the sword. Leah, however, kills the cultists with a surge of magical power, forcing Maghda to kill Cain and flee with the stranger. Cain, before dying, repairs the sword and tasks the protagonist with returning it to the stranger. The protagonist pursues Maghda into the bowels of King Leoric's dilapidated torture chambers underneath his manor, rescuing the stranger and returning to him his sword after a violent fight with the Butcher, a powerful demon. The stranger's memories are recovered, and it is revealed that he is the arch-angel Tyrael, the Aspect of Justice. Disgusted with his fellow angels' unwillingness to protect humanity from the forces of Hell, Tyrael cast aside his divinity to become a mortal and warn Sanctuary about the arrival of the demon lords Belial (Lord of Lies) and Azmodan (Lord of Sin).
The protagonist, Leah, and Tyrael travel to the city of Caldeum. The protagonist leaves to track down Maghda at Alcarnus as per orders from Cmdr. Ashaera, while Leah and Tyrael search for evidence of Belial in the city sewers. The protagonist heads to Khasim Outpost to try and pass the gate, but a suspicious man tells him/her to speak with Cpt. Davyd in the Command Post. When the hero walks in, Maghda thinks he/she was given as a sacrifice to Belial, but the hero cleverly states that the Lord of Lies sent her there as bait. Offended by the insult, Maghda orders the Imperial Guards (Deceiver demons in disguise) to mince the hero. Thankfully, Cpt. Davyd and the Iron Wolves reclaim Khasim Outpost from the serpent demons, and the hero is given access to Alcarnus. After freeing all of the prisoners at Alcarnus, the hero fights Maghda in her lair and destroys her, avenging Cain, then returns to Caldeum where Leah has learned that her mother, Adria (the witch of Tristram from the original game) is still alive.

The protagonist aids Leah in rescuing Adria from the city's sewers. Adria reveals that the key to stopping the forces of hell is the Black Soulstone, which can trap the souls of the seven Lords of Hell and destroy them forever. The protagonist resurrects the soul of the traitor Horadrim, Zoltun Kulle, in order to recover the Black Soulstone, who reveals that it is hidden in his archives. After recovering Kulle's body and some of his blood, so that he can open his lair, the protagonist is forced to defeat him after he attempts to take the soulstone for himself. Upon returning to Caldeum, the protagonist finds the city under attack by Belial's forces. Adria and Leah fight their way to the palace with the aid of the protagonist, revealing Belial as having taken the form of the young Emperor of Caldeum to deceive them, and eventually defeat him. Leah traps his soul within the Black Soulstone, freeing Caldeum, after which she receives a vision of the demon lord Azmodan, who is invading Sanctuary from the crater of Mount Arreat (destroyed by Tyrael in Diablo II) in order to retrieve the black soulstone and empower himself, becoming the Prime Evil.

The protagonist travels to Bastion's Keep with Tyrael, Leah and Adria to find it under attack by Azmodan's army. After defeating the demon Ghom, the Lord of Gluttony, the protagonist travels to crater of Mount Arreat to confront Azmodan. Tyrael assists the protagonist in reaching the demonic gate protecting the crater, and destroys it with his sword. The protagonist traverses the depths of Arreat's inner core to destroy the Sin Hearts, which empower Azmodan and his armies. Azmodan's consort Cydaea, the Maiden of Lust, attempts to protect the hearts but is defeated. The protagonist confronts and defeats Azmodan, and Leah seals his soul in the black soulstone. With all seven lords of hell trapped within the stone, Tyrael states that the war will be ended if the stone is destroyed. The protagonist returns to Bastion's Keep, but finds that Adria has betrayed them. Adria reveals she has been serving Diablo from the beginning, and that Leah's father is Leoric's son Aidan, the Dark Wanderer (the Warrior player character from the first game and Diablo's reincarnate body in Diablo II), who was possessed by Diablo. Adria sacrifices Leah and uses the Black Soulstone to resurrect Diablo. Now in possession of all the souls of the Lords of Hell, Diablo becomes the Prime Evil, and begins an assault on the High Heavens.

The protagonist arrives in the High Heavens to find it already under attack. Imperius, the Aspect of Valor, blames the protagonist and Tyrael for their downfall, causing Tyrael to give in to despair. The protagonist meets Itheriel, the Aspect of Fate, who instructs them to rescue Auriel, the Aspect of Hope, from Rakanoth, the Lord of Despair, in the Library of Fate, west of the Gardens of Hope. After rescuing Auriel and returning hope to the forces of Heaven, the protagonist finds Tyrael, who has overcome his despair. Together, they attempt to stop Diablo from reaching the Crystal Arch, the source of power for the forces of Heaven. Diablo is defeated and his physical manifestation destroyed. The Black Soulstone is shown falling from the High Heavens, apparently still intact. After the battle, Tyrael decides to rejoin the High Heavens as the new Aspect of Wisdom, but remains a mortal, dedicated to building a permanent alliance between angels and humans.