Of Love and Other Demons opens with a letter from the author explaining the genesis of the story. As a young cub reporter working in Cartagena, Colombia in 1949, García Márquez was asked to cover the emptying of the burial crypts of a historic convent called Santa Clara, where generations of bishops and abbesses had been laid to rest. While witnessing this event, García Márquez recalls, "the stone shattered at the first blow of the pickax, and a stream of living hair the intense color of copper spilled out of the crypt...attached to the skull of a young girl." Startled by the discovery, he remembers the legend his grandmother told him as boy about "a little twelve-year-old marquise with hair that trailed behind her like a bridal train, who had died of rabies caused by a dog bite and was venerated in the towns along the Caribbean coast for the many miracles she had performed."

Against the background of the lush, coastal tropics, García Márquez creates the story of an impossible, yet undeniable, love. Of Love and Other Demons is is set in a South American seaport during the colonial era, the home of bishops and viceroys, enlightened thinkers and Inquisitors, lepers and pirates. Sierva María de Todos los Ángeles, the rebellious only child of a decaying noble family, has been raised by her father's slaves in their quarters behind his mansion. On her twelfth birthday she is bitten by a rabid dog and made to withstand therapies indistinguishable from tortures. Believed to be possessed, Sierva María is imprisoned in a convent, where she meets Father Cayetano Delaura, who has been sent to oversee her exorcism. Father Delaura, a protégé of the bishop, is unprepared for the transfiguring passion that Sierva María awakens in his soul. Of Love and Other Demons is the story of their love: improbable, deeply moving, and defying - even in death - the constraints of reason and faith.