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Federer and Del Potro will meet as the rain-plagued event stretches into a Monday for the second straight year.
Federer is one win from his 16th Grand Slam title and his third major of the season after winning Roland Garros and Wimbledon.
Del Potro handed Nadal his first straight-sets loss in a five-set match since the 2008 Australian Open semi-finals, when Jo-Wilfried Tsonga beat him by a similar margin. Nadal lost to Andy Roddick in straights in the second round six years ago in New York.
Del Potro ended a four-match losing streak to Nadal this spring at Miami and is the only player to have beaten the Spaniard more than once this year.
'I can't believe this,' said the stunned winner. 'It's difficult to speak at the moment. This is my favourite tournament. I cannot believe this moment. I'm so excited. I'm close to achieving my dream to win this tournament.'
Six-time Grand Slam winner Nadal had just under 24 hours to rest for the semi after his quarter-final was not concluded until Friday afternoon during a dry spell amid two days of rain.
Del Potro won his place Thursday, with two full rest days.
He becomes the sixth Argentine to play a Grand Slam final, following Guillermo Vilas, Guillermo Coria, Gaston Gaudio, Mariano Puerta and David Nalbandian. Vilas won the US Open in 1977, when the event was played on clay.
'This is the best match I've ever played,' said Del Potro, 48-11 on the season.