Six hundred years have passed since a nuclear holocaust resulted in widespread death, mutation, and the destruction of knowledge across the world. The Order of St. Leibowitz is one of the few groups that works to maintain and rediscover what little knowledge of the old world that remains through their collection of documents known as the Memorabilia.

Brother Francis is an acolyte in the Order of St. Leibowitz. He must complete his days of fasting and contemplation in the desert to determine if he is called to become a full monk in the Order. One day an old Jew shows up and after some conversation, helps Francis find a stone to complete the makeshift shelter he is building. He marks the stone, and moves on. Francis, upon taking the stone to complete his shelter, discovers a hidden room in the ruins nearby. In it, he finds actual writings from Leibowitz himself, and evidence of Leibowitz wife's remains.

Despite the amazing discovery, Brother Francis is not allowed to take his vows, as the abbot does not want his story of the mysterious traveler and the remains to impact the full canonization of St. Leibowitz in the catholic church. Many years later, and after numerous desert vigils, Brother Francis becomes a monk and works at restoring a blueprint he found in the underground room. He takes the original and the restored version to New Rome for the canonization of Leibowitz. Along the way, bandits steal the restoration (believing it to be the original). Francis takes the original to the Pope in New Rome and the Pope gives him gold with which to purchase the restoration.

While waiting for the bandit who stole the restoration to come so he can buy it back, Brother Francis is murdered. The old traveler who he had met on his first vigil comes and buries Francis' body.

Six hundred years pass, and we meet a new abbot in the Order of St. Leibowitz. Science and knowledge has advanced some, in particular in the country of Texarkana through a man named Thon Taddeo. Taddeo, learning that the Order appears to have documents from the pre-deluge period, travels there. He studies and learns much from the documents, and returns to his country. War is coming soon, thanks to the king of Texarkana, but Taddeo only cares for science, even if he must support an evil dictator to gain more knowledge.

Benjamin, who seems to be the same old traveler who met Brother Francis in the desert, is friends with the Abbot of the Order.

Six hundred more years pass, and the world has come again to the nuclear age. Sensing that a second nuclear holocaust is imminent, the church initiates a program that will send the Memorabilia of the Order, along with enough priests and monks to baptize and continue the faith, into outer space. A single nuclear bomb is set off in the capital of Texarkana, and hundreds of sick and irradiated people travel to the monastery to get treatment.

The Abbot allows for the doctors to set up in their monastery, but only if they promise to do no more than the law requires in respect to informing citizens of their right to euthanasia. That is, the doctor must not encourage them to assisted suicide. A theological and ethical debate ensues, but the doctor agrees. A more intense debate occurs when the Abbot must speak with a mother (and her infant) who are suffering greatly from radiation poisoning.

More bombs drop and the monastery is destroyed. The Abbot, dying, sees a local two headed mutant woman.