Ex-fighter pilot Ted Striker (Robert Hays) became traumatized after an incident during the war, leading to his fear of flying. Recovering his courage, Striker attempts to regain the love of his life from the war, Elaine (Julie Hagerty), now a stewardess. In order to win her love, Striker overcomes his fear and buys a ticket on a flight she is serving on, from Los Angeles to Chicago. However, during the flight, Elaine rebuffs his attempts.
After dinner is served, many of the passengers fall ill, and Dr. Rumack (Leslie Nielsen) quickly realizes that one of the meal options gave the passengers food poisoning. The stewards discover that the pilot crew, including Captain Oveur (Peter Graves) and Roger Murdock (Kareem Abdul-Jabbar), have all come down with food poisoning, leaving no one aboard to fly the plane. Elaine is instructed by the Chicago control tower supervisor Steve McCroskey (Lloyd Bridges) to activate the plane's autopilot a large blow-up doll named "Otto" which will get them to Chicago but will not be able to land the plane. Elaine realizes that Striker is their only chance, and he is convinced to fly the plane, though he still feels his trauma will prevent him from safely landing the plane.
McCroskey, after hearing Striker's name on the radio, sends for Striker's former commander, Rex Kramer (Robert Stack) to help talk him down. As the plane nears Chicago, Striker neglects to check the oil temperature which damages one of the engines while a bad thunderstorm reduces visibility, making the landing even more difficult. Thanks to Kramer's endless stream of advice, Striker is able to overcome his fears and safely land the plane with only minor injuries to some passengers. Striker's courage rekindles Elaine's love for him, and the two share a kiss while Otto takes off in the evacuated plane after inflating a female autopilot doll.