In the near future, the Moon has been colonized and supports a space station on its surface. A lunar shuttle known as Mayflower One is being rushed to launch from Houston. The head of the ground crew, The Sarge (Chuck Connors), does not like what is occurring, but defers to airline management.On the flight crew are Captain Clarence Oveur (Peter Graves), navigator/co-pilot Unger (Kent McCord), and first officer/flight engineer Dunn (James A. Watson Jr.). Also on board is computer officer Elaine Dickinson (Julie Hagerty). Having dumped Ted Striker (Robert Hays), Elaine is now engaged to Simon Kurtz (Chad Everett), a member of the flight crew, and Ted is committed to an insane asylum. He was declared mentally incompetent in a lawsuit following a test flight that Ted piloted and in which the lunar shuttle crashed. Ted believes that the lawsuit was meant to silence him regarding dangerous safety issues related to the lunar shuttle. He is again haunted by his actions during World War II - specifically the loss of his entire squadron above Macho Grande - resulting in a relapse of his drinking problem. When Ted learns of the lunar shuttle's upcoming launch, he escapes from the asylum and buys a ticket for the flight.During the flight, Mayflower One suffers a short circuit, causing the artificially intelligent computer, ROK 4000, to go insane and send the shuttle toward the Sun. Unger and Dunn attempt to deactivate the computer, but are blown out of an airlock. Oveur attempts to stop the computer, but ROK 4000 gasses him. Simon abandons Elaine and leaves in the sole escape pod. Once again, Ted is called upon to save the day, but he must first figure out how to wrest control of the shuttle from the computer. Air traffic controller Steve McCroskey (Lloyd Bridges) reveals that passenger Joe Seluchi (Sonny Bono) has boarded with a bomb in a briefcase, intent on committing suicide to provide an insurance payout for his wife. Ted manages to wrestle the bomb from Joe, uses it to blow up ROK 4000, and sets course for the Moon as originally intended.The computer's destruction results in collateral damage to the shuttle; the flight is not exactly out of danger. On the way to the moon, flight control shifts to a lunar base under the command of Commander Buck Murdock (William Shatner). Contemptuous of Ted because of Macho Grande, he nonetheless agrees to help and they manage to land the shuttle safely on the Moon. Ted and Elaine rekindle their relationship and are married at the end. After the wedding, Joe looks into the cockpit and asks for his briefcase back. A post-credit message - "Coming from Paramount Pictures: Airplane III" - inspires Murdock to remark "That's exactly what they will be expecting us to do!"