In 1977, college graduates Harry Burns (Billy Crystal) and Sally Albright (Meg Ryan) share a contentious car ride from Chicago to New York, during which they argue about whether men and women can ever truly be strictly platonic friends. Ten years later, Harry and Sally meet again at a bookstore, and in the company of their respective best friends, Jess (Bruno Kirby) and Marie (Carrie Fisher), attempt to stay friends without sex becoming an issue between them.

Easily excitable Neal Page (Steve Martin) is somewhat of a control freak. Trying to get home to Chicago to spend Thanksgiving with his wife (Laila Robins) and kids, his flight is rerouted to a distant city in Kansas because of a freak snowstorm, and his sanity begins to fray. Worse yet, he is forced to bunk up with talkative Del Griffith (John Candy), whom he finds extremely annoying. Together they must overcome the insanity of holiday travel to reach their intended destination.

After a gentle alien becomes stranded on Earth, the being is discovered and befriended by a young boy named Elliott (Henry Thomas). Bringing the extraterrestrial into his suburban California house, Elliott introduces E.T., as the alien is dubbed, to his brother and his little sister, Gertie (Drew Barrymore), and the children decide to keep its existence a secret. Soon, however, E.T. falls ill, resulting in government intervention and a dire situation for both Elliott and the alien.