Humbert Humbert, a European literary scholar, describes the premature death of his childhood sweetheart, Annabel Leigh. He suggests his unconsummated love for her caused his fixation with "nymphets" (girl-children aged 9 to 14 that he finds sexually attractive). He indulges in his sexual fantasies by pretending to read a book in a public park and being aroused by nymphets playing near him, as well as by visiting a prostitute who he believes to be 16 or 17 and imagining her to be three years younger. After a close call with the police when he requested a nymphet-aged girl from a pimp, Humbert marries an adult woman with childish mannerisms, Valeria, for safety. His marriage with Valeria dissolves, and after another visit to a psychiatric ward after a mental breakdown, he moves to the small New England town of Ramsdale to write.
Humbert fantasizes about meeting and eventually fondling the 12-year-old daughter of an impoverished family from whom he agreed to rent, buying an expensive bag of toys before meeting the McCoo family, only to find that their house burned down. A "Mrs. Haze" offers to accommodate him instead, and Humbert visits her residence reluctantly out of politeness, as "the only reason for [his] coming at all [to Ramsdale] had vanished." He plans to decline the widowed Charlotte Haze's offer until he sees her 12-year-old daughter, Dolores (born 1935), known as "Lo", "Lola", or "Dolly". He immediately becomes infatuated with her, citing her uncanny resemblance to Annabel, and agrees to stay at Charlotte's house only to be near her daughter, whom he privately nicknames "Lolita".
While Lolita is away at summer camp, Charlotte, who has fallen in love with Humbert, tells him in a letter that he must either marry her or move out to avoid embarrassment. Humbert agrees to marry Charlotte in order to continue living near Lolita. Charlotte is oblivious to Humbert's distaste for her, as well as his lust for Lolita, until she reads his diary. After learning of Humbert's true feelings and intentions, Charlotte plans to flee and send Lolita to a reform school, she threatens to expose Humbert as a "detestable, abominable, criminal fraud." Fate intervenes on Humbert's behalf: as Charlotte runs across the street in a state of shock, she is struck and killed by a passing car.
Humbert retrieves Lolita from camp, pretending that Charlotte has been hospitalized. Rather than return to Charlotte's home, Humbert takes Lolita to a hotel. Humbert plans to use a sleeping pill to drug Lolita and rape her while she is unconscious. As he waits for the pill to take effect, he wanders through the hotel and meets a man who seems to know him. Humbert excuses himself from the strange conversation and returns to the hotel room. There, he tries molesting Lolita but finds that the sedative is too mild. Instead, she initiates sex the next morning, after explaining that she had slept with a boy at camp. Later, Humbert reveals to Lolita that Charlotte is dead, giving her the choice of accepting her stepfather into her life on his terms or facing foster care.
Lolita and Humbert drive around the country, moving from state to state and motel to motel. In order to keep Lolita from going to the police, Humbert tells her that if he is arrested, she will become a ward of the state and lose all her clothes and belongings. He also bribes her with food, money, or permission to attend fun events in return for sexual favors, though he knows that she does not reciprocate his love and shares none of his interests. After a year touring North America, the two settle down in another New England town, where Lolita is enrolled in a girls' school. Humbert becomes very possessive and strict, forbidding Lolita to take part in after-school activities or to associate with boys. Most of the townspeople see this as the action of a loving and concerned, though old-fashioned, parent.
Lolita begs to be allowed to take part in the school play, and Humbert reluctantly grants his permission in exchange for more sexual favors. The play is written by Mr. Clare Quilty. Quilty is said to have attended a rehearsal and been impressed by Lolita's acting. Just before opening night, Lolita and Humbert have a ferocious argument, and Lolita runs away while Humbert assures the neighbors everything is fine. He searches frantically until he finds her exiting a phone booth. She is in a bright, pleasant mood, saying that she tried to reach him at home and that a "great decision has been made." They go to buy drinks and Lolita tells Humbert she doesn't care about the play and wants to resume their travels.
As Lolita and Humbert drive westward again, Humbert gets the feeling that their car is being tailed and becomes increasingly paranoid, suspecting that Lolita is conspiring with others in order to escape. She falls ill and must convalesce in a hospital while Humbert stays in a nearby motel. Lolita disappears from the hospital, with the staff telling Humbert that her uncle checked her out. Humbert embarks upon a frantic search to find Lolita and her abductor, but eventually gives up. During this time, Humbert has a two-year relationship (ending in 1952) with a woman named Rita, whom he describes as a "kind, good sport" who "solemnly approve[s]" of his search for Lolita, while knowing none of the details.
Humbert receives a letter from Lolita, now 17, who tells him that she is married, pregnant, and in desperate need of money. Humbert goes to see Lolita, giving her money in exchange for the name of the man who abducted her. She reveals the truth: Clare Quilty checked her out of the hospital after following them throughout their travels and tried to make her star in one of his pornographic films. When she refused, he threw her out. She worked odd jobs before meeting and marrying her husband, who knows nothing about her past. Humbert repeatedly asks Lolita to leave her husband, Dick, and live with him, which she refuses to do. He gives her a large sum of money anyway. As he leaves she smiles and shouts goodbye in a "sweet, American" way.
Humbert finds Quilty, whom he intends to kill, at his mansion. Eventually, Humbert shoots him dead, and exits the house. Shortly afterwards, he is arrested for driving on the wrong side of the road and swerving. The narrative closes with Humbert's final words to Lolita in which he wishes her well, and reveals the novel in its metafiction to be the memoirs of his life, only to be published after he and Lolita have both died. The novel's fictional foreword states that Humbert Humbert dies of coronary thrombosis after completing the manuscript. It also states that "Mrs. Richard F. Schiller" (Lolita) died giving birth to a stillborn girl on Christmas Day, 1952, at the age of 17.