The novel begins with the report of the emptying of the crypts at the Convent of Santa Clara. This is where a skull is found of a twelve-year-old girl with a huge amount of copper colored hair growing out of it. The author remembers the legend of the twelve-year-old girl from two hundred years ago who died of rabies. The scene then shifts to a city in colonial New Grenada, in what is now Columbia. Sierva is the twelve-year-old girl, and is going to the market on her birthday. She is slightly bitten on the ankle by a dog that is later found to be infected with rabies. Sierva is being raised by the women of the slave quarter in the house of her father, the Marquis. She is wild and difficult to deal with in any case.

The news slowly circulates that several of the other people who are bitten have died of rabies, which is always fatal. The Marquis, Sierva's father consults with Dr. Abrenuncio, who says that since the girl was only lightly bitten on the leg, she may never develop rabies. The girl seems to be all right and her father becomes closer to her. Then one day Sierva develops a slight fever. The Marquis panics and sends her to all sorts of quacks and faith healers who give her treatments that are painful and torturous. The local Bishop hears of this spectacle and sends for the Marquis. The Bishop asks that the girl be brought to the convent of Santa Clara for an exorcism, since sometimes demons take over a person under the cover of a disease. The weak Marquis cannot consult with his wife Bernarda, who is on drugs, and decides to submit to this decision. Sierva is surrendered to the convent. After singing with the convent slaves, Sierva is arrested and thrown in the convent prison. The Abbess declares that Sierva is possessed by demons. Sierva suffers various assaults and screams and fights. This is used as evidence against Sierva that she is possessed by demons.

The Bishop appoints his confidant, Father Cayetano Delaura, to be the exorcist of the girl. Father Cayetano is a thirty-six-year-old priest who is the Bishop's librarian. Cayetano becomes fascinated with the girl, Sierva, and then falls in love with her. Cayetano becomes friendly with Sierva and tries to have her freed, but the Bishop refuses. Cayetano talks to the Marquis and to Dr. Abrenuncio, suspected of being an atheist, about how to free Sierva from the convent. Cayetano then goes to the girl. When he is attacked by Sierva, he flees in a state of love and terror. Cayetano tells the Bishop what has happened to him, and Cayetano is stripped of his privileges and sent to work in a lepers' hospital.

Cayetano finds a way to sneak into the convent at night through a tunnel to see Sierva, and he comes back many nights. They secretly kiss, fall in love, and plan to marry. Then, this is interrupted when the exorcism of Sierva begins. Sierva is tied up and subjected to harsh treatment at the hands of the Bishop. Sierva screams and acts the part of one possessed. The next day a friendly part-African priest is assigned to exorcise her, but then he mysteriously dies. The other prisoner, Martina Laborde, sees Cayetano coming and going through the tunnel and uses it to escape. The convent authorities discover the tunnel and seal it. Now Sierva is subjected to a harsh exorcism and there is no one to comfort her. Sierva dies, and miraculously hair begins to grow again from her shaved head.