Dr. Juvenal Urbino, the City of the Viceroy's most esteemed doctor, is sent to examine the body of his close friend and finest competitor at chess, Jeremiah Saint-Amour, who has killed himself at the age of sixty so that he will not grow old. The Doctor returns home and discovers that his pet parrot has escaped from his cage to the top of the mango tree outside. Dr. Urbino climbs a ladder to the branch on which the parrot sits, but just as he grasps the parrot, the Doctor falls to his death. Flo rentino Ariza professes, for a second time, his "eternal fidelity and everlasting love" to the Doctor and his wife, Fermina Daza. Fermina is horrified by such an insensitive display, and, for the first time, realizes the magnitude of the "drama" sh e had provoked at the age of eighteen.
Although Fermina Daza may have erased Florentino Ariza from her memory, he has not stopped thinking of her since their long, troubled love affair ended fifty-one years, nine months, and four days ago. Florentino first meets Fermina when he delivers a tele gram to her father, Lorenzo Daza, who is notorious for his shady dealings. After watching Fermina, always accompanied by her Aunt Escolástica, walk to school each day from the Park of the Evangels, Florentino works up the courage to approach her o ne day. He asks that she accept a letter from him, but she refuses because she is obligated to get her father's permission. He demands that she "get it," which she does the following week. Florentino decides to give her a subdued note (instead of the sixt y-page letter he had originally written) in which he resolutely declares his love for her. He is in agony as he awaits her reply, but is overjoyed when Fermina finally answers approvingly.
In the two years that follow, Fermina and Florentino see one another only in passing, though they write love letters daily. Florentino proposes marriage to Fermina, and again her reply is favorable. Fermina is caught writing a love letter by the Mother Su perior at her academy and is expelled. Lorenzo finds love letters in Fermina's room and as punishment, banishes Escolástica and forces Fermina to accompany him on a long journey, not to end until she has forgotten about Florentino. On the journey, Fermina meets and befriends her older cousin, Hildebranda Sánchez, who helps Florentino and Fermina communicate via telegraph messages.
Florentino hardly recognizes Fermina upon her return from the long journey, because, now seventeen, she has matured into a woman. He sees her in the Arcade of the Scribes, and approaches her. When Fermina sees him, she is suddenly disgusted with him and w ith herself for ever having been foolish enough to love him. Coolly, she tells Florentino to "forget it." Florentino tries once more to woo Fermina, but to no avail. In the fifty-one years, nine months, and four days that follow, not once does Florentino have the chance to speak or see his beloved Fermina in private. Initially, he vows to save his virginity for only Fermina, but after being seized by Rosalba aboard a ship to a faraway city, he turns to sex to ameliorate the pain he feels at having lo st Fermina. He returns home, intent upon once again making her his own. Meanwhile, he conducts affairs, however secret, with innumerable women, though he is rumored to be a homosexual.
Dr. Urbino courts Fermina, who resists his affections. Lorenzo Daza forces the Doctor upon his daughter, and she reluctantly concedes. When Florentino hears that Fermina is to marry a prestigious physician, he vows to make himself worthy of her. His uncle , Don Leo XII Loayza, gives him a job at the River Company of the Caribbean, of which, after thirty years, Florentino becomes President. Fermina and the Doctor honeymoon in Europe for three months. When Fermina returns, she is pregnant with her first child. Despite his determination to win Fermina, Florentino continues his lustful affairs with other women, whom he finds at the transient hotel and on the trolley. It is on the trolley that he meets Leona Cassiani, whom he mistakes for a whore. Leona asks him only for a job, which he gives to her.
Florentino realizes that he must wait, without violence or impatience, for Dr. Urbino to die before he can win over Fermina. When in public, he is greeted by Dr. Urbino with familiar cordiality, though Fermina lends only a courteous glance or smile, and w ithout memory of their past. Fermina and the Doctor appear to be a very happy couple, but in reality they are quite dissatisfied. The unhappy but stable marriage is rocked when Dr. Urbino conducts a four-month affair with Barbara Lynch, though he ends it when Fermina confronts him with her knowledge of it. Infuriated by her husband's infidelity, Fermina goes to live with Hildebranda on her ranch. The Doctor arrives at the ranch unannounced to take Fermina, who is overjoyed by his arrival, home with hi m.
Upon the Doctor's accidental death, Florentino, now elderly, abruptly ends his affair with fourteen-year-old América Vicuña and, at Dr. Urbino's wake, professes his "eternal fidelity and everlasting love" to Fermina. After having banished him from her home in anger, she sends him a hateful letter. He responds with a meditation on life and love, which helps her overcome her grief. Gradually, after a letter correspondence, they rekindle their relationship and spend afternoons together in Fermina's ho me. Florentino asks Fermina to accompany him on a river voyage, and she accepts. On the voyage, Florentino and Fermina finally make love. As the ship reaches its last port, Fermina sees people she knows and frets that if they see her with Florentino, it w ill cause scandal. Florentino orders the Captain to raise the yellow flag of cholera, which he does. There remain no passengers on aboard but Fermina, Florentino, the Captain, and his lover. No port will allow them to dock because of the supposed cholera outbreak aboard, and they are forever exiled to cruise the river.