The story chronicles the plan of a cardinal-deacon and his closest allies to unite the remaining independent nations in North America against the Empire, and to restore power to the Church.
The main character of the novel is Brother Blacktooth "Nimmy" St. George, a monk at Leibowitz Abbey located in the desert north of modern day Santa Fe, New Mexico.
Brownpony requires a translator in his travels in order to deal diplomatically with the unruly Nomad hordes who occupy the Great Plains; the WildDogs, Grasshoppers and Jackrabbits.
During the conquest of Hannegan II the Jackrabbit horde was subdued along with a minority of Grasshopper clans, having since been forced to settle as farmers and abandon their nomadic ways.
The Church had been exiled from the holy city of New Rome (modern day St Louis, Missouri) in previous decades because of an invasion by the Emperor (or "Hannegan") of Texark.
Upon arriving at the settlement of Arch Hollow on the way to Valana, they are accosted by genetically handicapped Gennies or Gleps, escapees from The Valley of the Misborn.
They attempt to have sex but find Ædrea is unable due to surgery performed on her when she was a child to prevent her from being raped by marauding nomads, outlaws or soldiers, leaving her with a tiny vagina.
During their time in Arch Hollow it is revealed that Chur Hongan is the nephew of the WildDog war sharf and a distant relative of the Hannegans of Texark, themselves having been nomad outlaws who conquered the city.
She reveals she did the same thing in the dark after their previous encounter in the cellar and is now late for her period, believing giving birth will undo the surgery performed on her.
The nomads ritualisticly consume their deceased leader as part of the funerary traditions and Brownpony is disturbed to find his friend Father e'Laiden partaking.
Chur Hongan tries to assist Brownpony in his trial by alerting him to changes in wind direction to avoid the radiation but he eventually falls asleep after he sees a vision of the Buzzard of Battle.
Chur Hongan and the Grasshopper sharf Hultor Bram each undergo the same breeding pit trial to determine who will become Lord of the Three Hordes.
The Weejus women determine Chur Hongan to be the recipient of the Wild Horse Woman's favour while pronouncing that Hultor Bram has been visited by the Night Hag and will soon die.
Meanwhile, Blacktooth is press ganged into the Valana militia, now led by Cardinal Hadala joined with New Jerusalem spooks on a mission to deliver arms to the Watchitah Nation gleps of the Valley of the Misborn.
Brownpony declares an effective crusade against the Texark Empire, leading an alliance of Nomads, New Jerusalem Spooks and the Valanian Militia to recapture New Rome and excommunicating the Hannegan's cardinals.
He escapes the dungeon and falls into a drugged stupor, truly awakening in the damaged St. Peter's Cathedral, where he finds Brownpony and his last surviving bodyguard, Wooshin.
Their reunion is disrupted by the arrival of a Nomad warrior, who informs them that the attack on Hannigan City failed and the last loyal portions of the crusading army are departing.
He warns them to flee as a Texark relief force approaches New Rome but Brownpony refuses and seats himself on the papal throne, the first Valana pope in decades to do so.
A sick Blacktooth is plagued by visions of Saint Leibowitz and the Wild Horse Women holding his twin children as he searches for Ædrea.
After completing Canticle, Miller signed for another book with Lippincott, but the project apparently fell apart when the publisher offered only a small advance of $1,000.
More than a decade later, Bantam publisher Lou Aronica learned of the draft, convinced Congdon to send him a copy, and quickly encouraged Miller to resume work on the novel.