A Plague Tale: Innocence takes players to the 14th century during the Hundred Years' War. Young Amicia de Rune is lucky enough to come from a royal family, but all is not well in her life. She does not get to see her younger brother Hugo de Rune mostly because he has been ill since birth, and he is always being cared for by her mother. Things take a turn for the worst when a terrible rat plague strikes, making normal life impossible. When the Inquisition comes around seeking Hugo, Amicia is forced to flee with him, taking them on a frightful journey involving plenty of creeping around, puzzle-solving, and dealing with a mysterious rat plague.