The film begins in a battle between two men, which ends with one of them, Clare Quilty (Peter Sellers), being shot. The shooter was Humbert Humbert (James Mason), a 40-something British professor of French literature. The film then turns to events 4 years earlier and goes forward as Humbert travels to Ramsdale, New Hampshire, a small town where he will spend the summer before his professorship begins at Beardsley College, Ohio. He searches across the town for room to let, being tempted by widowed, sexually famished mother, Charlotte Haze (Shelley Winters) to stay at her house. He declines until seeing her beautiful 14-year-old daughter, Dolores Haze (Sue Lyon), affectionately called Lolita (hence the title). Lolita is a soda-pop drinking, gum-chewing, overtly flirtatious teenager, with whom Humbert falls hopelessly in love.
In order to become close to Lolita, Humbert accepts Charlotte's offer and becomes a lodger in the Haze household. Soon, however, Charlotte announces that she will be sending Lolita to an all-girl sleep-away camp for the summer. On the morning of departure, Humbert receives a love confession note from Charlotte, asking Humbert to leave at once. The note says that if Humbert is still in the house when Charlotte returns from driving Lolita to camp, then he must join Charlotte in marriage. Humbert willingly marries Charlotte days later. After the wedding and honeymoon, Charlotte discovers Humberts diary entries describing his passion for Lolita, and has an emotional outburst. She threatens to leave forever, taking Lolita far away from Humbert. While Humbert hurriedly fixes martinis in the kitchen to smooth over the situation, Charlotte runs outside, gets hit by a speeding car, and dies.
Several days later Humbert drives to Camp Climax to pick up Lolita, and as they travel from hotel to motel across the United States, they begin a sexual relationship. In public, they act as father and daughter to avoid suspicion. During their travels, Humbert tells Lolita that her mother is not sick in hospital (as he had previously told her), but dead. Deeply saddened and affected, she stays with Humbert, believing he is her only comfort. Months later, Humbert and Lolitas car trips are followed by the same car. As Lolita becomes sick from the common cold, she is hospitalized, and eventually kidnapped by the follower, Clare Quilty (played by Peter Sellers), a famous playwright, on whom Lolita had a crush for some time. Years after the kidnapping, Humbert receives a letter from Lolita, now 17, who tells him that she is married, pregnant, and in desperate need of funds. Armed with a gun, Humbert, still driving Charlotte's car, visits his young obsession and gives her the money she was due from her mother's estate. He also asks her to leave with him, but she refuses. During their conversation, Lolita explains that her husband, a nearly deaf war-veteran and the father of her unborn child, was not her abductor, whereupon Humbert offers to give her all the money he has if she will reveal the man's identity. Lolita complies, saying that she had really loved Clare Quilty, but that he threw her out after she refused to perform in a pornographic film he was making.
Leaving Lolita forever, Humbert surprises Quilty at his mansion. Quilty goes mad when he sees Humbert's gun. After a mutually exhausting struggle for it, Quilty, now insane with fear, merely responds politely as Humbert repeatedly shoots him. He finally dies with a comical lack of interest, expressing his slight concern in an affected English accent. Humbert is left exhausted and disoriented. Arrested for murder, he writes the book he entitles Lolita or, The Confessions of a White Widowed Male, while awaiting trial.