The American, a daughter of Haitian parents and ranked at 296, clinched a famous 5-7, 6-4, 6-4 win to register her first victory at a Grand Slam, two years after her only other major appearance, when she was defeated in New York by Kim Clijsters.
"The crowd really helped me. Sam is a great champion and I watched her when she won the US Open. Today she didn't play her best match and I played the best match of my career," said Duval.
Stosur, 12 years older than her opponent and who parted with long-time coach David Taylor on the eve of the US Open, saved a match point in the ninth game of the decider.
Duval, roared on a by a packed Louis Armstrong court, squandered two more match points before taking victory at the fourth time of asking with a sweeping forehand.
Stosur was undone by 56 unforced errors and 10 double faults.
Duval goes on to meet Slovak veteran Daniela Hantuchova for a place in the last 32.
US Open: Former champion Sam Stosur dumped out by American teenager
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