A Canticle for Leibowitz follows a Catholic monastic order in its 18-century effort to preserve the legacy of human knowledge as mankind repeatedly destroys itself in nuclear flames.

Six centuries ago, the world suffers a Flame Deluge and violently rejects all learning, in the Simplification. A widowed former weapons scientist, Leibowitz, gathers followers and establishes a monastic order dedicated to preserving remnants human knowledge. Leibowitz is martyred and by the 26th century is up for canonization. The world has returned to a hunter-gatherer economy, and the Catholic Church struggling against marauding barbarians and shamans. Young Francis Gerard of Utah and fellow novices spend Lent scattered in the desert, enduring a strict vocational retreat before professing in the Albertine Order of Leibowitz (AOL.) An ancient stranger invades Francis' peace and discloses a long-buried fallout shelter. Novices embellish the story, which the brutal Abbot Arkos wants suppressed. After many tries, Francis is professed and made an apprentice copyist. He spends 15 years illuminating the Leibowitz blueprint he found in the shelter, and is invited to New Rome for the canonization. During the trek, Francis loses his prized illumination to robbers but preserves the original, which he presents to the Pope. En route home, an arrow to the forehead kills Francis, who is buried by the stranger he first met wandering the deep desert.

By A.D. 3174, Hannegan II of Texarkana is bent on reuniting North America and secular scholars are shaking off the Church's monopoly on learning. Among the foremost is Hannegan's brilliant cousin, Thon Taddeo Pfardentrott. Troubled by premonitions of trouble, Dom Paulo rules the abbey. Brother Kornhoer reinvents artificial light and feuds with the old-fashioned librarian, Ambruster. Paolo visits a hermetic old friend, Benjamin, who considers himself the last remnant of Israel, old enough to have buried the murdered Francis. Benjamin waits for a Messiah but does not expect him. Refreshed, Paolo returns to the abbey to await Taddeo's extended visit, which lays the foundation for decades of work fitting the puzzle together. Taddeo foresees a blood crisis to break the bonds of cultural inertia, Paulo fears another Flame Deluge, and Benjamin sadly concludes Taddeo is not the Messiah. War breaks out, Hannegan incurs New Rome's wrath by murdering its envoy, and as Taddeo prepares to leave the abbey, Paulo argues scientists have a brief window for exercising moral authority over rulers, but the scholar's mind is closed. He believes the secular world should take over the Order's mission. Buzzards again circle battlefields, doing what Nature intends.

By A.D. 3781, darkness has given way to light but radiation levels are rising after a recent detonation in Asia. Under Dom Jethrah Zerchi, the Order has been recruiting space veterans, including Brother Joshua. A figure looking like Benjamin appears in the refectory, proclaiming an omen, and a two-headed mutant, Mrs. Grale, discomforts the monks. As diplomatic talks stall and a full-fledged exchange appears imminent, Zerchi forces Joshua to decide whether he will accept ordination and lead 27 monks to Centauri Colony. After an agony in the abbey rose garden, Joshua agrees, and the party departs for New Rome. The abbot faces a moral dilemma when the Green Star organization asks to perform triage on radiation victims in the abbey courtyard. Dr. Cors does not practice euthanasia, but does advocate a quick, merciful death for those terminally exposed. To Zerchi, this is a mortal sin. The battle focuses on a young Catholic widow and her wailing, horribly burned, infant. Zerchi sends picketers to the nearby euthanasia site, and is so outraged, when he loses his two innocent souls he punches Cors and is spared jail only by agreeing to end the protests. Zerchi is hearing Mrs. Grale's confession when Leibowitz Abbey is blown apart by a nearby detonation and, trapped in rubble, he learns to practice what he has stoically preached. Rachel assumes control of the shared body, refuses conditional baptism, and administers a last communion to the dying but mystified priest. The monks escape as the earth is engulfed in flames, leaving only deep-water sharks alive.