The novel is set in a post apocalyptic world that has been ravaged by a nuclear war that is also referred to as the Flame Deluge. The fallout of this conflict led to an uprising that scorned the use of technology and knowledge (given that those were what led to the war), which was led by the self-proclaimed Simpletons who burned books and executed literate individuals.
One such literate individual however, Issac Edward Leibowitz, the titular character, decides to engage in the preservation of knowledge through smuggling books and memorizing and copying them. He eventually amassed a large number of supporters and formed the Albertian Order of Leibowitz.
The events of the novel are split into three sections spanning 18 centuries and chronicle the activities of the Order.
Fiat Homo
The first section of the novel takes place in the 26th century and follows a member of the Order, Brother Francis Gerard. On a vigil in the desert, he chances upon an ancient nuclear shelter that housed certain handwritten notes by Leibowitz. However, this discovery is not looked upon kindly by the Order for fears of interrupting Leibowitz's canonization and Brother Francis returns to the desert to complete his vigil.
Years later, Leibowitz's canonization is being investigated by the God's Advocate and the Devil's Advocate of the Catholic Church, who visit the shelter in which Leibowitz's writings were found. Leibowitz is canonized and Brother Francis is sent to New Rome to represent the Order at the Mass. However, on his journey there, he is robbed of one of the gifts he brought for the Pope. He is later killed by a group of genetically mutated subhumans who shot him in the face.
Fiat Lux
The second section of the novel takes place in the 32nd Century. Knowledge and technology from before the Flame Deluge is still scarcely understood and is being preserved by the Order. This section follows the lives of Thon Taddeo Pfardentrott, a secular scholar and his cousin Hannegan, the mayor of Texarkana.
At his cousin's behest, Thon visits the Order to study the technology that they have been preserving and restoring. During his time with the Order, he finds that they have made progress and have developed an electrical generator. Armed with this newfound information, he returns to Texarkana.
During this time, Hannegan forges an alliance with a number of surrounding city-states that collectively form the Kingdom of Larendo under the guise of defense against barbarians. However, he actually intends to consolidate his power to launch an attack on Denver. His plan is discovered by Mosignor Apollo, the Church's representative in Texarkana who reports this plan to the Church. For his betrayal, Apollo is executed and Christianity is outlawed in Texarkana. Unable to do much else, the church excommunicated Hannegan.
Fiat Voluntas Tua
This section takes place in the 38th century. Humanity has achieved interstellar travel and have colonized planets beyond the solar system. The Order has updated its purpose to the preservation of all knowledge instead of just the writings of Leibowitz.
This section chronicles the conflict between two Earth superpowers and the actions of the abbott of the order, Dom Jethras Zerchi. On Earth, the Asian Coalition and the Atlantic Confederacy have been embroiled in a cold war for the better part of the last century. As tensions escalate, Zerchi puts the Church's secret plan into action and instructs Brother Joshua to depart on spaceships to spread the Church and the Order out to the human colonies in response to the threat of nuclear war on Earth.
However, conflict breaks out and the Order's abbey collapses form the blast of a nearby nuclear explosion. Zerchi is unable to escape and is trapped by the collapsing abbey walls. He dies quickly from his injuries. However, just as all this happens, Brother Joshua and the last members of the secret mission are able to board a spaceship and leave the system right as the nuclear explosions begin.
