As a worried mother comforts her desperately ill son in Rio de Janeiro, the child's physician, Dr. Decosta, assures her that, thanks to the new night flying schedule of the Trans-Andean European Air Mail, which is being inaugurated that evening, they will receive a life-saving serum the next day. In Santiago, Chile, pilot Auguste Pellerin leaves for Buenos Aires, the airline's headquarters, with the medicine. Rough weather makes his flight a harrowing one, and the shaken Pellerin is grateful to land safely, even though the airline's stern director, A. Riviére, fines him for being late. Over the objections of Daudet, the airline's president, and other board members, Riviére determines to make the night flight program successful and downplays the dangers of South America's unpredictable weather. Riviére is a harsh taskmaster who deeply respects his pilots even while driving them ever harder, and his no-nonsense tactics intimidate his more easy-going inspector, Robineau. Meanwhile, pilot Jules Fabian and his wireless operator, H. Guimet, have left Punta Arenas in the southern tip of Chile and are alarmed by the appearance of a sudden rainstorm. Fabian's wife Simone is waiting at home for him and has prepared a special dinner to celebrate his first night flight. Although Guimet wants to land in nearby Bahia Blanca, Argentina, Fabian decides to persevere, for he knows that they will be fined if they are late. They radio to headquarters that they are flying blind, but their transmission is cut off. As Simone grows more concerned, Fabian is driven farther off-course by the worsening storm. After Robineau returns to the office following a dinner with Pellerin, Riviére reprimands him for socializing with the pilot, and forces him to punish Pellerin for a fabricated offense as a lesson. Riviére also calls upon a Brazilian pilot to take the mail to Rio, and the pilot's wife pleads with him not to go. Simone, who realizes that her husband has been dangerously delayed, arrives at headquarters after Riviére refuses to give her any information over the telephone. While Simone waits anxiously for news, Fabian and Guimet, who believe that they have passed the worst of the storm, are forced to jump from their plane when it runs out of fuel. The storm has driven them over the ocean, however, and both men jump to their death in the churning water. At the airport, Simone realizes that Fabian is dead and hysterically accuses Riviére of treating the pilots like machines. Riviére explains that the night mail must go through regardless and, after overcoming more resistance from Daudet, sends the Brazilian pilot to Rio. Despite his wife's worries, the pilot makes his run safely and on time, and even though he believes that the only value of night mail is that someone in Paris can get a postcard on Tuesday instead of Thursday, its real value is proven when the serum reaches Dr. Decosta and the ill child is saved.