When asked if vignette-type stories will feature, the developers responded that 'twenty years is a long time.' Similarly, the game may explore key events in the series's lore ( Destruction's End is one such example).

The player's character is a hero who allies themselves with the remnants of the Horadrim, aiming to prevent the enemies of Sanctuary from reclaiming and controlling the Worldstone. The game's plot will include what happened to humanity after Tyrael destroyed the Worldstone, how Tyrael was able to reform in Heaven, the activities of Deckard Cain, why Malthael abandoned Heaven, how the Demon Hunters were founded, what the golden age of Westmarch was like and the schemes of Adria and Maghda. Simultaneously, a fledging Coven has emerged, its cultists roaming the land and spreading corruption wherever they trod. The game's main antagonist is Skarn, Herald of Diablo, who seeks to gather the Worldstone fragments to resurrect his master and reignite the Eternal Conflict. Although destroyed, its fragments carried Baal's corruption with them, wreaking havoc across Sanctuary.

The catalyst of the plot is the destruction of the Worldstone. Many of the game's plot points have their origins in the Eternal Conflict. The game starts in the year 1270, though as of the Destruction's Wake update, the timeframe has extended to 1272. Diablo Immortal will tell stories set between the events of Diablo II: Lord of Destruction and Diablo III.

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