1. The game's main protagonists are the Ghosts, a force of U.S. Special Operations personnel trained to conduct clandestine missions behind enemy lines. The unit is led by retired U.S. Army Captain Elias Walker (Stephen Lang). He is joined by his sons Logan and David "Hesh" Walker (Brandon Routh), along with a trained German Shepherd named Riley, Captain Thomas A. Merrick (Jeffrey Pierce), and Sergeant Keegan P. Russ (Brian Bloom).

2. The game is set within a fictionalized, hyper-connected version of Chicago, Illinois, which is managed through a centralised system called CtOS, developed by fictional company Blume. The single-player story is told through Aiden Pearce, a highly skilled grey hat hacker who can hack into the CtOS, granting him access to various electronic systems, either to obtain and control information or to interact with these systems to his advantage.

3. 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.

4. The story revolves around an undead traveler trying to find a cure for the curse of undeath, who is branded with the Dark sign much like the player character of the previous game.[10] The game's director has mentioned that the sequel is not directly linked to its predecessor story-wise, although they are set in the same world. The director also stated that the concept of time will factor into the story. The story takes place in the land of Drangleic, full of souls to help undead maintain their humanity while fighting the curse of the undead.[11]