Most of Piranesi is set in the House, a mysterious, labyrinthine otherworld comprised of infinite halls spread across three levels: the flooded Drowned Halls, the cloud-filled Upper Halls, and the Middle Halls, where Piranesi lives. Aside from Piranesi, the House is inhabited by birds, skeletons, and a number of statues, all of which Piranesi converses with and considers his companions. For a long time, the House's only other human visitor is the Other, who meets with Piranesi several times a week to discuss his goal of uncovering "The Great and Secret Knowledge," a powerful truth he believes the house contains.
As the novel unfolds, it becomes clear that the House coexists with the real, everyday world. According to the Prophet, a strange old man Piranesi is surprised to find wandering the House's halls, the House is a distributary world, formed by ideas that flow out of the actual world. In this way, the house is a repository of sorts for the wisdom of the ancients. It represents humanity's connection to the past. Fittingly, time functions differently within the house; while in the outer world, it's the 2010s, Piranesi marks the passage of time not by the stipulations of the Gregorian calendar but by significant events he observes and records. Toward the end of the novel, Piranesi escapes the House and returns to the real world, where he struggles to adjust to the hustle and bustle of 21st century human life.