Breakfast at Tiffany's documents the year-long friendship of a New York writer, whose name is never mentioned, with his neighbor Holly Golightly. The story is presented as the writer's recollections approximately twelve years after the conclusion of the friendship. Reminded of Holly by a visit with another old friend, Joe Bell, who is in possession of a photograph of an African carving that resembles Holly, the narrator relates that he occupied the same upper East-side brownstone as Holly over ten years ago. Shortly after he moves in, he notices Holly late one summer night when she loses her key and rings another tenant, I.Y. Yunioshi, to let her into the building, causing a commotion. He describes her as just under nineteen years old, thin and chicly dressed with a boyish haircut. When Holly begins ringing the narrator to let her into the building late at night, he is intrigued. He enjoys observing Holly at trendy restaurants and night clubs around town, and often watches her feeding her nameless cat or playing country songs on her guitar from his fire escape window. He even takes note of her trash, which contains numerous love letters from overseas soldiers.
In September, Holly visits the narrator's apartment in the middle of the night after one of her lovers turns vicious in bed. The two converse and Holly reveals that she has been paying weekly visits to Sally Tomato, a notorious gangster who is incarcerated in Sing Sing prison. Tomato's lawyer, O'Shaughnessey, pays Holly $100 per visit to convey "the weather report" - encrypted messages - between the two men. The narrator reads Holly one of his short stories, which she finds uninteresting, and the two fall asleep on his bed. She leaves abruptly when he asks her why she is crying in the middle of her sleep.
Despite this hostile exchange, Holly and the narrator reconcile, and she invites him to a party at her apartment. There, the narrator meets O.J. Berman, a Hollywood agent who relates the story of his unsuccessful attempts to make Holly the teenage runaway into Holly the movie starlet. The narrator also meets Rusty Trawler, a millionaire famous for his checkered family past who appears to be conducting an affair with Holly, and Mag Wildwood, an eccentric model who drunkenly insults Holly and passes out on the living room floor. Holly is upset with the narrator for not seeing Mag home safely, but he continues to observe Holly from a distance. He takes particular notice when Mag moves into Holly's apartment and often sees the two women leaving the apartment in the evenings accompanied by Rusty Trawler and Jose Yberra-Jaegar, a Brazilian politician to whom Mag is engaged.
Holly and the narrator reconcile when he shares with her the exciting news that his first short story has been published. While she feels that he should be more commercially ambitious as a writer, she nevertheless takes him out to celebrate. The two spend a day at Central Park, where they exchange stories about their childhoods, the narrator noticing that Holly's story is a fabrication. They later shoplift Halloween masks from Woolworth's. Shortly thereafter, the narrator spots Holly entering the public library. Following her inside, he observes that she is consulting books about the politics and geography of Brazil. Despite the deceptions and secrets that seem to trouble Holly's relationships with others, the two become close. On Christmas Eve, the narrator and Holly exchange gifts: he presents her with a St. Christopher's medal from Tiffany's, her favorite New York landmark, and she gives him an antique bird cage she knew he had admired, making him promise that he will never use it to imprison a "living thing."
Holly's inner circle crumbles in February, when Mag suspects Holly of having an affair with Jose on a group trip to the Florida keys. Upon her return, she and the narrator argue and she suggests his writing "means nothing" and is un-sellable. Protective of his artistic integrity and offended by Holly's crass commercialism, the narrator doesn't speak to Holly until later that spring, when the arrival of Doc Golightly sparks his sympathy for his former friend. Doc Golightly asks the narrator for help with his search for Holly, and reveals that he is Holly's husband. He tells the narrator the story of their marriage in Tulip, Texas, which occurred when Holly was only fourteen after she and her brother, Fred, escaped the cruel foster family they were placed with following their parents' death. Doc further informs the narrator that Holly's real name is Lulamae Barnes, and that she ran away from Doc and his extended family despite his willingness to indulge her often expensive demands. The narrator seems to re-unite Doc and Holly successfully, but Doc returns to Texas the next morning.
When the narrator reads that Rusty Trawler has married Mag Wildwood, he rushes home to tell Holly. He finds Holly's apartment in an uproar, the sound of breaking glass emanating from behind the front door. Joined by Jose and a doctor, the narrator enters her apartment to see Holly sick with grief and rage. Jose reveals to the narrator that earlier that morning, Holly received a telegram informing her of her brother Fred's death in the war. Over the next few months, the narrator watches Holly transform into a domestic homebody as her romance with Jose dominates her life. She furnishes her apartment, learns to cook, and gains weight. Over one of her home-cooked meals, Holly confesses to the narrator that she is pregnant, and that she expects to marry Jose and live with him in Brazil. This wish becomes reality, and on September 30, the narrator is despondent to learn that Holly is leaving for Brazil the following week. She invites him to join her on a horseback ride through Central Park. The pair are enjoying their ride when the narrator's horse is deliberately provoked by a group of young boys. The horse gallops off wildly into New York traffic, and is finally halted by Holly and a mounted police officer. The narrator passes out in shock. Holly takes him back to his apartment and bathes him.
However, they are soon interrupted by the intrusion of their neighbor, Sapphia Spanella, who is accompanied by two police officers. The officers arrest Holly on charges of conspiracy with Sally Tomato and O'Shaughnessy. The arrest is publicized in all the major papers, and with the exception of O.J. Berman, who hires her a top lawyer, Holly's society friends are largely unwilling to help her. The narrator visits Holly in the hospital, where she is recovering from a miscarriage induced by her vigorous horseback riding on the day of the arrest. He brings her a letter from Jose, in which he notifies her that, because of his political reputation, he is unwilling to continue their relationship. An upset Holly confides to the narrator that she is nonetheless planning on skipping out on bail and escaping to Brazil. She asks the narrator to aid her in the escape.
That Saturday, the narrator collects a few of Holly's belongings, including her cat, and brings them to Joe's bar, where Holly is waiting. Joe calls a taxi, and the narrator accompanies Holly on the drive. She asks the driver to stop in Spanish Harlem, where she leaves her cat on the street. The narrator chastises Holly, who is soon overcome with grief and jumps out of the taxi to search for the cat, who is nowhere to be found. The narrator promises Holly he will return to the neighborhood to search for her cat, and Holly leaves. While the authorities soon trace Holly's flight to Rio, Sally Tomato's death in Sing Sing makes her indictment unnecessary. Aside from a single postcard from Buenos Aires, the narrator never hears from Holly again. However, keeping his promise, he finds Holly's cat, now safely at home in a Spanish Harlem apartment.