Harry and Sally first meet in 1977 when they share a car ride from the University of Chicago to New York City. They discuss their opposing views on relationships, with Harry believing men and women can't be friends due to sexual attraction, while Sally disagrees. Over the years, they bump into each other through various encounters, each time deepening their connection yet maintaining their own separate lives and relationships.

Years later, they become close friends, supporting each other through personal struggles and offering insights into their romantic misfortunes. As they spend more time together, they inadvertently challenge Harry's initial assertion about friendships between men and women, developing a deep bond that slowly begins to blur the lines between friendship and romance. Their evolving relationship forces them to reevaluate their feelings about love, companionship, and the nature of true friendship without realizing how much their lives have intertwined.