The Argentine giant, who won his only Grand Slam title in the city in 2009 by beating Federer in the final after seeing off Nadal in the semis, triumphed 7-5, 3-6, 7-6 (10/8), 6-4 in front of a spellbound Arthur Ashe Stadium crowd.
The 28-year-old will once again face world number one Nadal in the semi-finals today, a stunning achievement for a man who had saved two match points to beat sixth seed Dominic Thiem in the last 16.
Nadal, who will keep his world number one status following third seed Federer’s exit, had earlier defeated Russian teenager Andrey Rublev 6-1, 6-2, 6-2 in just 97 minutes.
It will be a sixth US Open semi-final for Nadal and 26th at the majors while Del Potro, the 24th seed, will be playing in just his fourth last-four match at the Slams.
For 36-year-old Federer, it was a first Slam loss of 2017 after he had captured the Australian Open and Wimbledon titles to take his career tally to 19.
“I served really good. I hit my forehand as hard as I could and I played a great match. I deserved to win,” said Del Potro who will be in his first Slam semi-final since Wimbledon in 2013.
“This feels like my home court. I played Rafa here in 2009 too. Hopefully I can get the same result on Friday.”
Del Potro, whose career was almost ended last year after undergoing four wrist surgeries, wrapped up the first set thanks to a break in the 11th game secured with a blistering crosscourt pass.
Federer, who had a 16-5 winning record over Del Potro ahead of the quarter-final, levelled the tie after breaking for a 3-1 lead in the second.
However, the match turned in the third set tiebreak when Del Potro saved four set points before a weary and error-riddled Federer dropped serve again to trail 3-2 in the fourth. Victory was Del Potro’s eight minutes short of three hours with a deep forehand as Federer was left to survey the wreckage of 41 unforced errors.
“It’s hard to explain, I didn’t play that badly,” said Federer.
Meanwhile, world number one Rafa Nadal provided Russian teenager Andrey Rublev with a tennis lesson , racing into the semi-finals of the US Open with a ruthless 6-1 6-2 6-2 win.
The 19-year-old, who grew up idolising Nadal and had the Spaniard’s poster pinned up on his bedroom wall was smiling from ear-to-ear as he posed for pre-match photos on Arthur Ashe Stadium court with his hero.
That would be the highlight of an eye-opening afternoon for the Russian youngster as Nadal showed no mercy during a one hour, 37 minute thrashing.
“I knew a great new generation coming and Andrey is one of these players that have a great future and I wish him all the best,” said Nadal, after clinching his spot in his 26th grand slam semi-final.
“It was a good match and obviously it was Andrey’s first quarter-finals and of course he played with some more mistakes than usual but for me it was an important victory winning the last two matches in straight sets.”
Once the match started it did not take long for Rublev’s grin to disappear. It was replaced by scowls and frustration as the 53rd-ranked Russian angrily yelled at himself for missed shots and occasionally slapped at his leg with a clenched fist.
Nadal, still stinging from a third-round upset by 18-year-old Canadian Denis Shapovalov in Montreal in August and with a spot in the semi-finals and a possible showdown with rival Roger Federer on the line, was fully focused on the task at hand.
While fans were still filing into Arthur Ashe, Nadal was wrapping up a clinical first set in 23 minutes.
Rublev offered some resistance to start the second but it was brief, Nadal breaking to go up 3-2 and again to close out the set. A relentless Nadal broke to open the third and when Rublev double faulted to hand him yet another break at 4-1, the dejected Russian simply bent over and let his racquet drop.
But Rublev was not done scolding himself, dropping into his chair during the changeover then hammering away at his foot with his racquet.
Nadal will take an 8-5 record over Del Potro into the semi-final where the winner will face either Kevin Anderson or Pablo Carreno Busta for the title.
“Juan Martin is a top player. When he’s playing well, it’s difficult to stop him. Probably the forehand is maybe the fastest on the tour,” said Nadal, who is chasing his second major of the year to add to his French Open.
Rublev, bidding to be the youngest man in 17 years to reach the semi-finals, had no complaints over his loss to Nadal.
“He gave me a lesson: 1, 2, and 2,” said the Russian, who lost 16 of the last 19 points of the opening set and finished with 43 unforced errors.