The novel is set in a parallel universe made up of hundreds of halls and vestibules, which triggers a gradual loss of memory and identity in newcomers.

Piranesi lives in a place called the House, a world composed of infinite halls and vestibules lined with statues, no two of which are alike.

Twice a week, Piranesi meets with the Other, a well-dressed man who enlists his help to search for a "Great and Secret Knowledge" hidden somewhere in the House.

The Other warns Piranesi that a sixteenth person, whom both call "16", may enter the House to do him harm, and that he must not approach 16 under any circumstances or he will lose his sanity.

While indexing his journals, Piranesi discovers references to entries he doesn't remember writing which include terms mentioned by the Prophet.

Arne-Sayles fostered a cult-like mentality among his followers and was eventually imprisoned for kidnapping a man named James Ritter.

After learning that a rare confluence of tides will soon flood the middle level of the House, Piranesi leaves a warning for 16, and discovers a message from her asking "Are you Matthew Rose Sorensen?"

Piranesi pieces the destroyed pages back together from scraps he finds in gull nests, and learns the true story of how he came to the House: he was Matthew Rose Sorensen, a journalist writing a book about Arne-Sayles.

Piranesi is Clarke's second novel, following her debut Jonathan Strange & Mr Norrell (2004), which sold 4 million copies worldwide and was adapted into a BBC miniseries of the same name in 2015.

"[19] Ron Charles of The Washington Post called it "infinitely clever" and praised Piranesi's acceptance of his imprisonment for unintentionally making the novel "resonate with a planet in quarantine" due to the COVID-19 pandemic.

[21] The title of the novel alludes to the 18th-century Italian artist Giovanni Battista Piranesi, who produced a series of sixteen prints entitled Imaginary Prisons which depict enormous subterranean vaults with stairs and mighty machines.

[28] Piranesi also contains allusions to the work of Jorge Luis Borges, in particular his short stories "The Library of Babel" and "The House of Asterion", which Clarke has discussed in an interview.

[29] Piranesi was adapted and abridged for BBC Radio 4, read by Samuel Anderson, and broadcast as ten 15-minute episodes in February 2022.

[30][31] In June 2024, it was announced that the American stop-motion studio Laika had acquired the rights to adapt the novel into an animated feature film, to be directed by Travis Knight.