Part one offers context for the subsequent parts of the book. At 12:00 pm on July 20, 1714 five people attempt to cross an ancient bridge on the road from Lima to Cusco. To no one's surprise, considering the Incas had erected the rope structure over a decade before, the bridge gave way and fell under their weight. A Franciscan monk named Brother Juniper who was approaching the bridge at that particular moment witnesses the event and deems it an act of God. He determines to prove the role of God's divine plan in the births, lives, and deaths of people by using these five people as a sort of case study.
Part two is about the life of Doña Maria, one of the victims of the collapse. She was born into the rich family of a cloth merchant and bears the title Marquesa de Montemayor. After an unhappy arranged marriage, she gives birth to her beloved daughter Clara. Despite her extreme love for the girl and her best efforts to demonstrate said love, Clara grows up cold and distant from her mother. Eventually she runs off with a Spaniard and moves to his country, where Maria writes her constantly. She writes so much that she excels at the craft, and her letters are studied in schools for centuries. When Maria hears that Clara is pregnant, she determines to travel to the shrine of Santa Maria de Cluxambuqua, and she takes along a girl from her convent, Pepita. During the journey Pepita is helpful but homesick and writes a letter to her Abbess about her loneliness. Maria gets her hands on the letter and questions Pepita about it. Pepita responds saying she tore it up because it was not a brave letter. Inspired by the girl's determination, Maria writes her own brave letter to her daughter. The two are travelling to the shrine when the bridge collapses and kills both of them.
The third part focuses on twins -- Esteban and Manuel. They both grew up in the Convent of Santa Maria Rosa (Pepita's convent) where they quickly become favorites of the Abbess. Inseparable from birth, they are so close that they invent a language between them that nobody else understands. Trouble strikes when Manuel starts writing love letters for Camila Perichole. He falls in love with her, but she's losing him to seduce other men. When Esteban learns of the relationship, he encourages Manuel to make his feelings known to her, but he refuses. Not long after Manuel cuts his knee on some metal, suffers an infection, and dies. After losing his brother, Esteban begins acting erratically and stops listening to the counsel of the Abbess. She introduces him to Captain Alvarado who agrees to take Esteban with him on his global travels. Estaban attempts suicide the night before they leave, and the captain talks him down by promising to purchase a gift for the Abbess before they depart. At the bridge on the way Lima Esteban crosses and dies, but the captain goes below to ferry his supplies across the river.
Part four is about Uncle Pio, Camila Perichole's servant and mentor. Born a bastard to a wealthy man in Madrid, he travels the world and studies literature and business. When he finds himself too caught up in the Spanish Catholic Church, he escapes to Peru. He meets twelve-year-old Micaela Villegas singing in a cafe one day and decides to become her agent. Through years of dedication she becomes the renowned Camila Perichole. As she matures into adulthood, she wants to become more of a lady. Uncle Pio and she begin an affair and become socialites, engaging frequently with Peru's Archbishop and Captain Alvarado. Eventually Camila decides Uncle Pio is limiting her social status and attempts to change her identity and leave him behind. By this point she has three children of her own. She contracts smallpox which ruin her face permanently. When Uncle Pio catches her trying to cover up the scars, she becomes so embarrassed that she refuses to talk to him again. She does grant him permission to take her son, Jaime, and teach him to become a singer as she was. On their pilgrimage, both Uncle Pio and Jaime die in the bridge collapse.
Part five returns to Brother Juniper's quest. Despite working six years on compiling the book, he does not arrive at any sort of provable evidence of God's involvement in the collapse of the bridge. He is unable to link the five people together. He publishes the book anyway out of faith, but it is soon condemned as heresy and ordered to be burned.
Wilder then describes the memorial service for the victims of the collapse. All the major players attend, including the Archbishop of Peru, Captain Alvarado, and the Abbess of Santa Maria Rosa de la Rosas. The Abbess feels hopeless over the loss of both twins and Pepita. Camila soon reaches out to her in an attempt to understand how's she's grieving and decides to stay at the convent. Even Clara travels from Spain to meet the Abbess and learn more about her mother. The old woman goes on caring for the ill and underprivileged until the day of her death.
