The story occurs mainly in an unnamed port city somewhere near the Caribbean Sea and the Magdalena River. While the city remains unnamed throughout the novel, descriptions and names of places suggest it is based on Cartagena with the addition of the Magdalena River which meets the sea at the nearby city of Barranquilla. The fictional city is divided into such sections as "The District of the Viceroys" and "The Arcade of the Scribes." The novel takes place approximately during the half century between 1880 and 1930. The city’s "steamy and sleepy streets, rat-infested sewers, old slave quarter, decaying colonial architecture, and multifarious inhabitants" are mentioned variously in the text and mingle amid the lives of the characters. Locations within the story include:
- The house Fermina shares with her husband, Dr. Juvenal Urbino.
- The "transient hotel" where Florentino Ariza stays for a brief time.
- Ariza’s office at the river company.
- The Arcade of the Scribes.
- The Magdalena River.