It is based on the 1931 novel of the same name which won the Prix Femina the same year, by French writer and pioneering aviator Antoine de Saint-Exupéry. Based on Saint-Exupéry's personal experiences while flying on South American mail routes, Night Flight recreates a 24-hour period of the operations of a fictional airline based on Aéropostale, Trans-Andean European Air Mail.
In South America, the daunting mountains and dangerous weather have hampered the operations of Trans-Andean European Air Mail, a 1930s-era airline. Charged with delivering a serum to stem an outbreak of infantile paralysis in Rio de Janeiro, Auguste Pellerin (Robert Montgomery) conquers his fears, but is reprimanded by the airline's stern director, A. Riviére (John Barrymore) for coming in late.
Determined to make the night flight program work, Riviére has sent pilot Jules Fabian (Clark Gable) and his wireless operator on another dangerous flight. The pair are caught in a torrential rain storm and when Madame Fabian (Helen Hayes) comes to the headquarters, she realizes that her husband is overdue. The two airmen, flying blind over the ocean, run out of fuel and choose to jump, but are drowned.
Riviére refuses to quit and orders a Brazilian pilot (William Gargan) to take the mail to Rio, but the pilot's wife (Myrna Loy) pleads with him not to go. Despite the dangers, the night mail is delivered on time. The pilot despairs that his flight only meant that someone in Paris can get a postcard on Tuesday instead of Thursday, but its real value is proven when the serum is also delivered and a child is saved.
Saint Exupéry's Vol de nuit, based on real-life events in South America, had won the 1931 Prix Femina, one of the main French literary prizes (awarded by a female jury). Prior to this award, he had been little known outside of the literary sphere, but as a result of the prize, received widespread recognition and attention from Hollywood.
Selznick realized that Oliver H.P. Garrett's original treatment was too heavily based on "the ground" and brought in John Monk Saunders, who had worked with him on The Dawn Patrol (1930), to add more flying scenes. Director Clarence Brown was dissatisfied with that version, so Selznick finally called on writer Wells Root to tighten up the final draft. Brown also was interested in an accurate portrayal of aviation, as he had been a World War I pilot. Night Flight utilized both studio and location shooting with the mountainous region around Denver, Colorado, filling in for the South American Andes. The recently retired U.S. Mail Douglas M-4 mail planes were featured as the Trans-Andean European Air Mail's primary aircraft.