On the fictional planet of Arbre, the great intellectual leaders - the avout - live separate from the rest of society in concents. They are called upon to lead pure lives, devoid of any Sæcular influence. In the Concent of Saunt Edhar, one teacher, Fraa Orolo, possesses forbidden technology. The protagonist, Fraa Erasmas, favors Orolo and keeps his secret. Orolo owns a video camera with which he's spotted an approaching alien spaceship. Unfortunately for everybody, he is discovered and banished from the planet, according to a rite called Anathem, for unlawfully possessing technology within the concent.
After Orolo is banished, Erasmas learns about his discovery of the aliens. Not long after, the aliens shine a laser form their ship upon Saunt Edhar, contaminating all of the residents. The leaders of the Sæcular Power evoke - or deploy - many from the consent, including Erasmas and Fraa Jad. They are supposed to attend a war council at the Concent of Saunt Tredegarh. After some encouragement from Fraa Jad, however, Erasmas and others set out to locate Fraa Orolo. When they find him at last, they learn that he has discovered a dead female alien and preserved her body for research, along with four vials of alien blood. Shortly after they all meet up, the men are forced to flee the area with the alien corpse because the alien ship launches a metal rod into a nearby volcano causing a deadly eruption. Orolo sacrifices himself to save the dead alien, an act which earns him the title of Saunt Orolo.
At Saunt Tredegarth, Erasmas finally attends the Convox, a council between both the avout and the Sæcular Power. They are all gathered to discuss the alien presence and how to respond. Using Orolo's samples, they conduct a great deal of research. Suddenly, Erasmas and his companions discover that the Convox has been inflitrated by alien spies and unmask the imposters. Jules Verne Durand is an emissary from the alien craft. He explains that there are two factions - the militaristic Urnud and Tro and the ruling, enlightened Fthos and Laterrans. Durand, on behalf of the Laterrans, wishes to negotiate for peace.
The concent is quickly evacuated. The council trains and deploys a handful of men to board the alien ship. Unkonwingly, they are equipped with neutron bombs intended to destroy entire planets. Only three men are given clearance to know the true purpose of the mission and given detonators, including Fraa Jad. Onboard the ship, the aliens are preparing their main weapon for use. Some of the avout successfully disable this weapon but die in the process.
The narrative becomes complicated here as multiple coexistent realities exist across the cosmos. In one story, Fraa Jad wakes Erasmas up from oxygen deprivation and leads him to the ship's command center. They are attacked, and Jad sets off a nuclear bomb killing everybody. Another parallel narrative shows Jad and Erasmas being taken to a peacetalk with the Fthos. Here they learn that the avant may have actually summoned the ship by their magical incantations hundreds of years in the making. Finally, one narrative shows Erasmas waking in the ship's sick bay. He is told that Fraa Jad died immediately after their launch, but he still remembers events to the contrary. Apparently the aliens can act in multiple parallel universes simultaneously, so they are living multiple parallel lives. In this sense, then, each of the narratives is equally real, but only one is followed through until the book's conclusion. Erasmas learns that the aliens and his own people held a joint funeral ceremony to mourn those lost in the conflict. They begin a discussion of peace between the two races. The aliens set the avant and the Sæcular Powers on equal footing in the ruling of the people. They also institute a Reconstitution which lifts many of the restrictions on the avout. Erasmas and his companions begin building a new concent, this one named after Saunt Orolo and his devotion to peace.
