The sixth-seeded del Potro is the first Argentine U.S. Open winner since Guillermo Vilas won in 1977.
Appearing in his first-ever Grand Slam final, the 20-year-old del Potro earned $1.6 million for winning the U.S. Open and an additional $250,000 for finishing third in the U.S. Open Series. He also received a convertible automobile.
Federer, the five-time defending champion, earned $800,000 for finishing second.
Del Potro is the first player to beat both Federer and former No. 1 Rafael Nadal in the same Grand Slam event.
Federer, 28, was trying to add to his men's record with a 16th Grand Slam title. It was the first time he lost to someone in a Grand Slam final other than Nadal. The last time Federer lost at the U.S. Open was against another Argentine, David Nalbandian, six years ago.
Federer was trying to become the first man since Rod Laver in 1969 to win three straight major titles in one year. The Swiss had won the French Open and Wimbledon.