As Love in the Time of Cholera opens, we find Dr. Juvenal Urbino responding to a house call. His friend, the photographer Jeremiah de Saint-Amour, has committed suicide. This really screws up the doctor's schedule, as instead of going to Mass like he usually does, he has to go visit Jeremiah's secret lover, who explains to him that Jeremiah committed suicide because he never wanted to be old.
Dr. Urbino returns home to find the servants trying to catch the household's talking parrot, who, as the narrator tells us, will cost the doctor his life. The doctor and his wife go to a luncheon to honor one of his pupils. When they return, the doctor tries to catch the parrot, which has flown into a mango tree. The doctor falls out of the tree and breaks his neck, which means that he'll unfortunately be missing Jeremiah's funeral, since he's dead.
Dr. Urbino's wife, Fermina, seems composed at the wake that evening. A man named Florentino Ariza, President of the River Company of the Caribbean, shows up and makes himself useful. At the end of the night, Florentino confesses to Fermina that he's in love with her, and has been for the past fifty years. No dice. Fermina angrily kicks Florentino out of the house.
The narrative backtracks in time over half a century, and we are introduced to the teenage Florentino Ariza. He works for a telegraph office, which allows him to catch a glimpse of the young Fermina Daza when he delivers a telegram to her father, Lorenzo Daza. From that day on, the lovesick Florentino sits in the park outside Fermina's house and pretends to read while he watches her walk to and from school.
Eventually, Florentino gets up the nerve to give Fermina a letter. After a month, he impatiently demands a response, and finally gets one. Unbeknownst to her father, Florentino and Fermina strike up a fevered correspondence and, after two years, he writes to ask her to marry him. Fermina agrees to a long engagement, which they hide from her father.
Lorenzo eventually discovers the letters and takes Fermina away on a long trip in the hopes that she'll forget her entirely inappropriate affection for the lowly telegraph operator. The lovers continue to communicate in secret and plan to marry as soon as Fermina gets back. When Lorenzo is convinced that his daughter has forgotten all about Florentino, they return to the city. Florentino is overjoyed, but when Fermina sees him again she falls out of love with him and calls off the wedding.
Next we're introduced to the young Dr. Juvenal Urbino, who's obsessed with eradicating cholera, the disease that killed his father. He's called to the Daza house to diagnose a patient – the young Fermina – and determines that she does not have cholera. It's not love at first sight, but the doctor develops a crush on Fermina, which her father encourages. Fermina's not too crazy about the idea, but her cousin Hildebranda thinks Dr. Urbino is sexy and that she should go for it.
When Fermina finally agrees to marry Dr. Urbino, the heartbroken Florentino goes away to work in another city. On the boat, a mysterious stranger accosts him in the dark and robs him of his virginity. He never discovers the identity of his first lover, but imagines her to be Rosalba, a fellow traveler. Florentino decides he doesn't want to take the job after all, and returns home so that he can continue to live in the same city as Fermina. He tries to forget her by sleeping with lots of women, starting with a widow who's staying in his mother's house.
Meanwhile, Fermina is enjoying her European honeymoon. She returns home six months pregnant. Dr. and Mrs. Urbino occupy the center of civic and social life in the city.
Determined to become worthy of Fermina while he waits for her husband to kick the bucket, Florentino works hard at his job at the River Company and is promoted. He also renovates his house, writes poetry, and continues to have scores of clandestine love affairs. One of his lovers, a married woman, is murdered by her husband when he discovers that she's been cheating on him. Then Florentino's mother dies.
According to the many anecdotes of married life that we read, Fermina and Dr. Juvenal Urbino's relationship has its share of problems, but in general they're pretty happy. They have two kids, and move into a new house in the suburbs so that Fermina can get away from her mother-in-law.
The new century brings technological and civic advances to the city. Florentino takes advantage of every official ceremony to catch a glimpse of his beloved Fermina. On an inaugural balloon trip to the coast, Fermina and her husband see cities abandoned due to the cholera epidemic and scores of banana plantation workers dead from a wound to the back of the neck. Fermina goes to live on her cousin's ranch in the country for a couple of years, until she discovers that her husband has had an affair with one of his patients. Eventually they make up, and Fermina moves back to town.
Everyone starts to get old. When his uncle retires, Florentino is promoted to President of the River Company of the Caribbean. At this point he doesn't have as many lovers, but he does begin an affair with fourteen-year-old América Vicuña, who has been sent to the city to study. He serves as her guardian, and no one suspects that they are having an affair. When Dr. Urbino dies and Fermina becomes available, Florentino tells América that he is to be married and puts an end to their romance. Florentino relentlessly woos Fermina through a series of letters. It works, eventually, and the two become friends.
A local tabloid publishes some defamatory stories about Fermina's father and intimates that her dead husband had been having an affair with her best friend. Seeking to escape the scandal, Fermina agrees to go on a river cruise with Florentino. She falls in love with him, and the river cruise becomes a sort of honeymoon for them, despite the fact that the river banks have been deforested and the villages they pass are depopulated due to cholera.
Florentino receives news that América has committed suicide after failing her final exams, and, once he has made sure no one has discovered the secret of their affair, pushes the thought of her to the back of his mind.
When the boat picks up passengers for the return journey, Fermina sees some people she knows and fears a scandal if it becomes known that she's taking a pleasure cruise so soon after her husband's death. In order to avoid making Fermina uncomfortable, Florentino orders the Captain to fly a yellow flag, signaling cholera on board the boat. With this excuse, the boat sails downriver without passengers or cargo, stopping only to pick up fuel and the Captain's girlfriend. When they get back to the city, no one wants to go home to the "horror of real life" (6.225). Instead, Florentino suggests that they keep sailing up and down the river "forever" (6.239).