Fermina and Florentino fall in love and carry on an illicit correspondence behind her father's back. Lorenzo finds out and takes Fermina away from the city so that she'll forget about Florentino, but they persist in communicating and make plans to marry as soon as she gets back. When she sees Florentino again, however, she realizes she doesn't love him and calls off the wedding. A wealthy, young doctor named Juvenal Urbino courts Fermina, and she ends up marrying him. They go on a honeymoon to Europe and start a family. Florentino, meanwhile, vows never to leave the city of Fermina Daza and to work to become worthy of her.
Fermina and Dr. Juvenal Urbino enjoy a happy marriage, for the most part, though they do have their share of marital conflicts. In the meantime, Florentino has a series of love affairs, all the while maintaining his devotion to Fermina Daza. He begins an affair with a teenage girl that he has promised to chaperone while she lives in the city. He worries about getting old and fears that either he or Fermina might die before Dr. Urbino does, thus preventing them from the happy reunion that he feels is inevitable. Finally, Dr. Urbino does die, but when Florentino professes his undying love to Fermina, she angrily kicks him out of her house.
Florentino changes his approach and writes Fermina a series of letters in a more impersonal and philosophical tone. She appreciates them, and eventually the two become friends. Florentino and Fermina manage to overcome the scruples of her children and take a riverboat cruise together. Though the countryside has been reduced to a wasteland and cholera and political violence have wiped out the coastal villages, the couple's love buzz is impervious to the morbidity of their surroundings. They're wrapped up in a love cocoon. Florentino even suppresses the knowledge that his teenage lover has committed suicide, and that it's probably his fault. When the cruise comes to an end, the couple chooses to continue sailing up and down the river "forever," rather than go back to their former lives in the city and the "horror of real life."