The unheralded Australian wildcard took down the 14th seed 3-6 6-1 6-2 6-2 on Thursday (Friday AEST) for the biggest win of his career.
Standing only 170cm high, Sweeny rose to the occasion to reach the third round of a grand slam for the first time and earn a minimum pay day of $US290,000 ($A402,750).
Ranked more than 100 placed below his world No.14 opponent, Sweeny was the player doing all the bossing.
He ran Musetti ragged and had the Italian looking in great distress when he required a medical time-out after falling behind a double break at 0-3 in the pivotal third set.
Even after clawing one break back, Musetti - who has made the Wimbledon and French Open semi-finals over the past two years - continued remonstrating animatedly to his courtside box.
Despite sporting a massive ice pack on his right elbow after his first-round win, Sweeny continued diving like Boris Becker for acrobatic volleys at the next.
And the 25-year-old battler was duly rewarded with a last-32 shot at another Italian, world No.22 Luciano Daredri on Saturday (AEST).
Sweeny was among four Australians chasing spots in the men's third round on day six at Flushing Meadows.
His great mate Tristan Schoolkate was also up against an Italian heavyweight and snatched the first set against fifth-seeded French Open runner-up Flavio Cobilli.
Cobolli hit back to take the next two sets, leaving Schoolkate to stage a comeback to continue his heady run from qualifying.
Two years after upstaging Novak Djokovic in the US Open's third round, Alexei Popyrin was locked in a tenise battle with Chilean Alejandro Tabilo for a place in the last 32 once again.
Popyrin and the 25th seed split the first two sets.
Australia's sixth seed Alex de Minaur was scheduled to plau Dutchman Botic van de Zandschulp on The Grandstand after Schoolkate's match. Â
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