Dusty Crophopper (Dane Cook) is a cropduster plane who works at a cornfield and practices aerobatic manuveurs in his spare time, dreaming of becoming a racer. His dreams are scorned by his boss, Leadbottom (Cedric the Entertainer) and his forklift mechanic friend, Dottie (Teri Hatcher), yet supported by his fuel truck friend, Chug (Brad Garrett). Dusty and Chug train for qualifiers for the upcoming Wings Across the World race. The night before the qualifiers, Dusty asks an elderly and reclusive navy war plane named Skipper Riley (Stacy Keach) to teach him how to fly well but Skipper refuses. Dusty enters the qualifiers, and although the audience mocks him for being a crop duster, he manages to wow them by his well-practiced flight maneuvers, but comes in 6th place and does not qualify. A few days later, a representative from the qualifier visits his town looking for Dusty and announces to him that he now placed 5th. This is due to the qualifier ahead of Dusty using an illegal fuel enhancement, getting him disqualified and Dusty replacing him.
Later in the morning, Skipper visits Dusty and tries to talk him out of racing, but when Dusty explains he wants to prove he’s more than just a crop duster, Skipper decides to mentor Dusty on his speed and agility. While in the midst of his training, Dusty admits that he has a fear of heights. Despite this, their training continues and when it is complete, Dusty heads off to the meeting of the race at John F. Kennedy Airport where he finds a friend in a crazy but loyal Mexican race-plane named El Chupacabra (Carlos Alazraqui) who soon falls in love with a beautiful French-Canadian racer named Rochelle (Julia Louis-Dreyfus), who shows little interest in him. Dusty then makes a rival of the arrogant and villainous 3-time winner plane Ripslinger (Roger Craig Smith), who rudely dismisses him as being only a crop duster. Dusty also falls in love with a racer plane named Ishani (Priyanka Chopra).
The first leg of the race is from New York to Iceland. Dusty’s refusal to fly high causes him to finish in last place. The second leg of the race is to Germany. Dusty shows good sportsmanship by saving another racer, Bulldog (John Cleese), from crashing when his eyes get squirted with oil from his propellers, winning Bulldog’s respect but finishing last again. The third leg is to an air base at Agra in India while the fourth leg is over Nepal. In India Ishani gives Dusty advice on how to fly low through the Himalayas by following some railroad tracks. However, he is forced to fly through a tunnel and narrowly avoids a head-on collision with a steam train, but miraculously finishes first in Nepal. Dusty realizes Ishani deliberately gave him bad advice to get a new propeller from Ripslinger and he shuns her.
The fifth leg is over the Hump (the mountains between northeast India and south China) to Shanghai, where Dusty gets into first place again. There, Dusty manages to help El Chupacabra win over Rochelle with a romantic song, which works a little too well.
The sixth leg is across the Pacific Ocean to Mexico. Ripslinger’s henchmen, Ned and Zed, destroy Dusty’s navigation antenna. Lost and low on fuel and unable to find Hawaii, Dusty is found by two Super Hornets who escort him to the USS “Flysinhower” (a reference to the real-life aircraft carrier USS Dwight D. Eisenhower (CVN-69)) which allows him to land and refuel and be repaired. While on the carrier, Dusty sees a hall of fame set up for Skipper’s squadron, but discovers that Skipper only flew one mission, which contradicts his previous reputation as a veteran of many battles. He then has to take off to try and beat an oncoming storm. The storm becomes very violent with enormous waves. Dusty gets distracted from flying due to his thoughts about Skipper and ends up crashing into the ocean but is rescued. He is flown to Mexico to his friends but he is severely damaged and may never fly again. Skipper confesses to Dusty that he did indeed fly only one mission in the Pacific theatre where his entire squad of trainees was killed in an attack on the Japanese Navy. Skipper was the only survivor, but torn by his guilt, he never trained another plane or flew again. Demoralized and heartbroken, Dusty begins to consider dropping out of the race, but is encouraged by his friends, racers and many of his newfound fans to continue and they all donate parts to have Dusty repaired.
The seventh leg is back to New York. With a change of heart and morale restored, Dusty becomes determined to win the race, but Ripslinger still won’t give up and plots to sabotage his chances of winning. He and his goons ambush Dusty, but are thwarted by Skipper, who overcame his guilt and came to help Dusty. When trying to catch up with Ripslinger, Dusty conquers his fear of heights when his engine starts losing power, forcing him to ride the jetstream when he recognises from clouds that a jetstream is overhead. Both he and Ripslinger make it to the finish line in New York and when it looks like Ripslinger will win, his ego gets the best of him and slows down to have his picture taken. Dusty seizes the opportunity and wins the race while Ripslinger crashes into some portable toilets. Dusty is congratulated by his friends and fans and Skipper thanks him for giving him the confidence to fly again. Skipper rejoins the navy on the Flysinhower with Dusty as his partner and they take flight together.