In the near future, the Moon has been colonized and supports a 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, does not like what is occurring, but he defers to the airline's management.
On the flight crew are Captain Clarence Oveur, navigator/co-pilot, Unger, and first officer/flight engineer, Dunn. Also on board is computer officer Elaine Dickinson. Elaine has dumped Ted Striker, and is now engaged to one of the flight crew, Simon Kurtz. Ted has in the meantime been 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 used to silence him, because he knew there were problems with the lunar shuttle that made it unsafe. He is once more haunted by his actions in "The War" – causing a relapse of his "drinking problem", specifically the events that took place over "Macho Grande", where he lost his entire squadron. When Ted reads of the upcoming lunar shuttle launch, he escapes the asylum and buys a ticket for the flight.
During the flight, Mayflower One suffers a short circuit, causing the artificially intelligent computer, ROK, to go insane and send the ship toward the Sun. Unger and Dunn try to deactivate the computer, but are blown out of an airlock. Oveur tries to stop ROK, but the computer gasses him. Simon abandons Elaine and leaves in the only escape pod. Once again, Ted is called upon to save the day, but first he has to figure out how to make the computer relinquish control. Steve McCroskey, the air traffic controller, reveals that a passenger, Joe Seluchi, had boarded Mayflower One with a bomb in a briefcase, intending to commit suicide so that his wife can collect on insurance money. Ted manages to wrestle the bomb from Joe, and uses it to blow up ROK and set course for the Moon as originally intended.
Using the bomb to destroy the computer causes collateral damage to the shuttle, so the flight is not out of danger yet. On the way to the Moon, control of the flight is shifted to a lunar base, commanded by Commander Buck Murdock. He has a high level of contempt for Ted because of Macho Grande, but agrees to help anyway. They manage to land the craft on the Moon. Ted and Elaine fall back in love and are married at the end. After the wedding, Joe looks into the cockpit and asks for his briefcase back.
A postcredit scene shows a screen that says "Coming From Paramount Pictures: Airplane III". Murdock is then seen saying "That's exactly what they'll be expecting us to do!"
Robert Hays as Ted Striker
Julie Hagerty as Elaine Dickinson
Lloyd Bridges as Steve McCroskey
Chad Everett as Simon Kurtz
Peter Graves as Captain Clarence Oveur
Rip Torn as Bud Kruger
John Dehner as The Commissioner
Chuck Connors as The Sarge
Richard Jaeckel as Controller #2
Stephen Stucker as Jacobs
Kent McCord as Unger
James A. Watson Jr. as Dunn
Wendy Phillips as Mary
Laurene Landon as Testa
Sonny Bono as Joe Seluchi
William Shatner as Commander Buck Murdock
Raymond Burr as The Judge
John Vernon as Dr. Stone
James Noble as Father O'Flanagan
Jack Jones as Lounge Singer
John Larch as Prosecuting Attorney
Lee Bryant as Mrs. Hammen
John Hancock as Controller #1
Oliver Robins as Jimmy Wilson
Louis Giambalvo as Witness
David Paymer as Court Photographer
Rick Overton as Clerk
Sam Anderson as Man in White
Leon Askin as Moscow Anchorman
Art Fleming as Game Show Host (reprising the role as the host of Jeopardy!)
Frank Ashmore as Controller #3
Pat Sajak as Buffalo Anchorman
Louise Sorel as Nurse
Sandahl Bergman as Lieutenant White
Burke Byrnes as Businessman
Michael Currie as Businessman #1
Bruce French as Officer #2
Richard Gilliland as Pervis
Hugh Gillin as Texan
David Leisure as Hallick
Gail Matthius as Educational Network Woman
Lee Patterson as Phoenix Six Captain
Hervé Villechaize as Little Breather
Lee Purcell as Mrs. Seluchi
Earl Boen as Doctor
Joyce DeWitt as Juror
Cindy Fisher as Forward Passenger
Monique Gabrielle as Schoolgirl
Kitten Natividad as Moral Majority Woman
John Paragon as Economy Flight Attendant
George Wendt as Ticket Agent
sequel to the 1980 film Airplane!
titled Flying High II: The Sequel in Australia, New Zealand, South Africa, Japan, and the Philippines