A Plague Tale: Requiem is an action-adventure game similar to its predecessor. The player assumes control of Amicia and must face against both soldiers from the French Inquisition and hordes of rats that are spreading the black plague. Gameplay is largely similar to the first game, though the combat system is significantly expanded. The game features a progression system in which the player will be awarded additional skills and abilities. Stealth players will unlock skills that allow them to sneak around more efficiently, while those who prefer a more lethal approach will unlock additional combat skills. Locations are also larger, giving players additional options to progress.

After escaping their devastated homeland, Amicia and Hugo travel far south to new regions and vibrant cities. There, they attempt to start a new life and control Hugo’s curse. But when Hugo’s powers reawaken, death and destruction return in a flood of devouring rats. Forced to flee once more, the siblings place their hopes on a prophesized island that may hold the key to saving Hugo.