Set in the year 1978, Barry Seal (Tom Cruise) works as a pilot for Trans World Airlines. He is married to Lucy (Sarah Wright) and has two children with her, with a third on the way. While at a bar one night, Barry is found by a man saying his name is Monty Schafer (Domhnall Gleeson). He is familiar with Barry's work as a pilot, but Schafer offers him a chance to make better money by taking on reconnaissance missions for the CIA in a smaller plane with cameras just south of the border. Schafer convinces Barry that he would be working for the good guys, but it would have to be kept completely secret, even from his own family. He then lets Barry take the plane out for a ride.
As he begins his new job, Barry starts making tapes documenting his travels and exploits. He flies over countries like Guatemala, El Salvador, and Honduras. Schafer is so impressed with the photos that Barry brings back to him, that he assigns Barry a new task of being a bag man between the CIA and General Manuel Noriega (Alberto Ospino) in Panama. On his mission, Barry meets the Medellin Cartel - Jorge Ochoa (Alejandro Edda), Carlos Lehder (Fredy Yate Escobar), and Pablo Escobar (Mauricio Mejia). They want to get their drugs into the United States, but the runway for the planes is too risky for most pilots. Barry takes his plane for a ride and almost crashes into the trees but manages to pull up and continue his flight with ease and get back to the U.S. without getting in trouble.
Barry now has the trust of the cartel. However, the DEA raid one of their compounds, and Barry is arrested. Schafer finds him in his cell and tells him that his house will get raided, and Lucy will most likely be brought in for questioning and be kept overnight. When Barry gets out, he goes home and urges Lucy and the kids to pack up their things so they can move. Despite Lucy's questioning, Barry insists he cannot tell her a thing, leading her to lose trust in him. The Seals move to Mena, AR. Barry is then given the assignment to move guns for the Contras, even being allowed to own his own airport and planes for the job. His first flight to meet with the Contras ends with them robbing his stuff instead of taking his guns. Barry calls Schafer to let him know that the Contras aren't interested in the guns. On his second trip, he meets with a cartel leader to negotiate sending the guns to the cartel instead. Barry brings guns to the cartel and ships their drugs to the U.S. and the Contras while trying his hardest to avoid being detected by the law.