In 1977, Harry Burns and Sally Albright graduate from the University of Chicago and share the drive to New York City, where Sally is beginning journalism school and Harry is starting a career. Harry is dating Sally’s friend Amanda. During the drive, Harry and Sally discuss their differing ideas about relationships; Sally disagrees with Harry’s assertion that men and women cannot be friends as “the sex part gets in the way”. At a diner, Harry tells Sally she is attractive, and she angrily accuses him of making a pass at her. They part in New York on unfriendly terms.
Five years later, Harry and Sally find themselves on the same flight. Sally is dating Harry’s neighbor Joe, and Harry is engaged to Helen, which surprises Sally. Harry suggests they become friends, forcing him to qualify his previous position about the impossibility of male-female friendships. They separate, concluding that they will not be friends.
Harry and Sally run into each other again in a bookstore five years later. They have coffee and talk about their previous relationships; Sally and Joe broke up because she wanted a family and he did not want to marry, and Harry’s wife Helen left him for another man. They take a walk and become friends. They have late-night phone conversations, go to dinner, and spend time together, discussing their love lives.
During a New Year’s Eve party, Harry and Sally find themselves attracted to each other. Even though they remain friends, they set each other up with their respective best friends, Marie and Jess. When the four go to a restaurant, Marie and Jess become fast friends and later become engaged. Over the phone, Sally tearfully tells Harry that her ex is getting married. He rushes to her apartment to comfort her, and they have sex; Harry leaves the next morning distressed. Their friendship cools until a heated argument at Jess and Marie’s wedding dinner. Harry attempts to mend his friendship with Sally, but she feels that they cannot be friends.
At a New Year’s Eve party that year, Sally feels alone without Harry by her side. Harry spends New Year’s alone, walking around the city. As Sally decides to leave the party early, Harry appears and declares his love for her. She argues that the only reason he is there is because he is lonely, but he lists the many things he realized he loves about her. They kiss and marry three months later, exactly 12 years and three months after their first meeting.
The plot also contains several interlaced segments throughout the film where fictitious older married couples narrate to the camera their stories of how they met. The last couple that is interviewed before the closing credits is Harry and Sally.