Two priests, Josef Kou Hiraga and Roberto Nicholas, are members of the Seat of the Saints, a secretive and elite bureau within the Vatican. Their mission is to investigate reported miracles around the world, separating divine phenomena from hoaxes, natural events, or far more sinister forces. Hiraga is a brilliant Japanese scientist and devout Catholic who seeks empirical evidence for the supernatural, while Roberto is an Italian scholar of ancient texts, cryptanalysis, and comparative theology. Together, they travel to remote locations to authenticate weeping statues, stigmata, and other holy events.

The series is set within the real-world hierarchy of the Catholic Church but expands into hidden corners of its operations. The Seat of the Saints operates with the authority of the Congregation for the Causes of Saints, sending its examiners wherever a miracle requires validation. Their work is supported by Lauren Di Luca, a genius hacker and imprisoned atheist forced to cooperate with the Vatican under threat of a poison anklet, and Archbishop Saul, their powerful and protective superior.

In their first major arc, Hiraga and Roberto are sent to Saint Rosario Church in the American Southwest to investigate a nun's claim of a virgin conception. The atmosphere is immediately hostile, filled with rumors of devil worship among the students at the attached boys' academy. They soon uncover a series of brutal ritualistic murders and a plot far more disturbing than simple fraud. The church is run by descendants of Nazi occultists who are using drugs and brainwashing to build a Fourth Reich, disguising their satanic rituals as Catholic worship. The examiners must use scientific analysis to expose the truth behind the supposed miracles, which range from chemically induced stigmata to a weeping statue caused by simple condensation.

A personal conflict underlies Hiraga's work. His younger brother, Ryota, suffers from a terminal bone cancer and lives in a German medical facility. Hiraga's desperate search for a scientific cure drives his relentless pursuit of truth, as he fears that if genuine miracles do not exist, there may be no hope for his brother. Roberto, meanwhile, carries the trauma of his childhood when his violent father murdered his mother and fled.

The story expands globally with arcs set in Africa and Europe. In Africa, the pair investigate an incorrupt corpse of a priest renowned for prophecies. There, they encounter Father Julia, a beautiful and saintly missionary who seems the embodiment of Christian charity. This case reveals the existence of Galdoune, an ancient and immensely powerful conspiracy that has operated since the Middle Ages. Galdoune pursues immortality through forbidden alchemy, genetic engineering, and cloning, conducting horrific experiments on isolated populations. Father Julia is revealed to be a high-ranking operative and artificial creation of this organization. He offers Hiraga a cure for his brother and Roberto access to Galdoune's vast libraries in exchange for their loyalty, an offer they refuse, though Julia secretly delivers the medicine to Ryota anyway as a gesture of complex intent. The overarching narrative follows the two priests as they repeatedly clash with Galdoune's machinations, uncovering their attempts to infiltrate and control the Vatican while confronting morally devastating situations where the line between holy and demonic is deliberately blurred by human evil.