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he game takes place in Sanctuary, the dark fantasy world of the Diablo series. Sanctuary was saved twenty years prior by unnamed heroes in Diablo II. Having survived that onslaught, Tyrael rewarded the heroes by sending them to safety. It is up to a new generation of heroes to face the forces of evil threatening the world.
The player character, known as the Nephalem, arrives in New Tristram to investigate a fallen star. One of the townspeople, Leah, asks the Nephalem to help find her uncle, Deckard Cain, who went missing in the Tristram Cathedral when the falling star struck it. The Nephalem rescues Cain and finds that the fallen star is a person. This stranger has no memories except that he lost his sword, which was shattered into three pieces. The Nephalem retrieves the pieces, but the witch Maghda captures Cain and the pieces, attempting to force him to repair the sword for herself. However, the Nephalem forces Maghda to flee, and she kidnaps the stranger instead. Cain, dying from Maghda's torture, uses the last of his strength to repair the sword and instructs the Nephalem to return it to the stranger. The Nephalem rescues the stranger and returns his sword, causing him to regain his memories: he is the fallen angel Tyrael. Tyreal reveals that he was disgusted with his fellow angels' unwillingness to protect humanity from the forces of Hell, so he cast aside his divinity to become a mortal, and came to warn Sanctuary about the arrival of the demon lords Belial and Azmodan.
To avenge Cain's death, the Nephalem tracks Maghda to the city of Caldeum, which is controlled by her master, Belial. The Nephalem kills Maghda, and rescues Leah's mother, Adria. Adria tells Tyrael and the Nephalem that the key to stopping the demons is the Black Soulstone, which can trap the souls of the seven Lords of Hell and destroy them forever. In order to obtain the Black Soulstone, the Nephalem resurrects the mad Horadrim, Zoltan Kulle. Kulle reveals its hiding place and completes the unfinished Soulstone, but is killed by the Nephalem after he attempts to steal it. The Nephalem kills Belial and traps his soul within the Black Soulstone, freeing Caldeum. As Leah studies in Caldeum's library to find more answers about the Black Soulstone and Azmodan, she receives a vision from Azmodan, who tells her that he is sending an army from the ruins of Mount Arreat to take the Black Soulstone for himself.
Tyrael, Adria, Leah, and the Nephalem journey to Bastion's Keep, the only line of defense between Azmodan's forces and the rest of Sanctuary. With Tyrael, Adria, and Leah staying behind to protect the Black Soulstone, the Nephalem pushes out from the keep and into Mount Arreat. The Nephalem kills Azmodan and traps his soul in the Black Soulstone. However, Adria betrays the Nephalem and takes the Black Soulstone with all the demonic souls inside. She reveals that she has been Diablo's agent from the beginning, and that everything she had done up until this point was part of her plan to resurrect him. She reveals that Leah's father is Diablo, making her the perfect vessel for his physical form. Using Leah as a sacrifice, Adria resurrects Diablo. However, now having the souls of all the Lords of Hell within him, Diablo becomes the Prime Evil, the most powerful demon in existence. Diablo begins his assault on the High Heavens, the defending angels being no match for him.
Tyrael and the Nephalem follow Diablo to the High Heavens, where the city is under attack. The defending Angels warn the Nephalem that Diablo is attempting to reach the Crystal Arch, which is the source of all of the angels' power. If Diablo corrupts the Crystal Arch, his victory over the High Heavens will be complete. The Nephalem encounters Diablo at the top of the Crystal Arch and eventually defeats Diablo, destroying him and the souls of the other demon lords permanently. After the battle, Tyrael decides to rejoin the High Heavens but remain a mortal. Since Diablo was defeated, an Angel of Justice is no longer needed. Instead, he becomes the new Angel of Wisdom, dedicated to building an alliance between angels and humans to confront evil.