Del Potro, the 6-foot-6 (1.98m) Tower of Tandil knows it will be a battle against 6-foot-10 (2.08m) Isner, who has blasted a tournament-leading 112 aces.
World No.1 Nadal saw off a battling Nikoloz Basilashvili, the first Georgian in a fourth round at the Flushing Meadows, 6-3, 6-3, 6-7 (6-8), 6-4.
His wins had all been on hard courts, including the US Open third round in 2015 in straight sets.
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"That's definitely the most important thing going on right now in my life, more important than this tournament, " Isner said.
Thiem opened his tournament in NY by thrashing Sofia champion Mirza Basic 6-3 6-1 6-4.
"We fought the whole match and I survived with my serve which was key".
The two traded points through the tiebreak with neither extending his lead beyond one until Nadal finally created the two-point margin necessary to win at 7-5 off of Thiem's serve.
The Spanish star cruised into a two-set lead on Sunday, seemingly fully recovered from the trauma of fighting back from a set and break down to Russia's Karen Khachanov on Friday.
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Federer then bested the tricky Benoit Paire 7-5 6-4 6-4, in a performance that was more workman-like than it was clinical. But Federer came back to put the game at deuce when Kyrgios hit one into the net.
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Anderson was staring elimination from the event and needed a swift improvement in his play to keep his tournament hopes alive in the third set.
"Last year whole stadium was full of Argentinians".
Anderson's improvement at the age of 32 has been inspiring, with the South African following up his slam breakthrough here 12 months ago by reaching the final of Wimbledon, beating Roger Federer along the way.
"Of course it's disappointing", Anderson said. "It wasn't meant to be".
He had won six of seven meetings against Thiem, including all six on hard courts.
This will be the 11th meeting between these two players but all previous encounters have come on clay so it will be fascinating to see how their games match up on a different surface.
The Austrian played a near flawless match, dropping just four points on his first serve and firing 42 winners. "A bunch of times I thought I hit pretty decent returns but he really punishes anything he has time on‚ and even sometimes when he doesn't have time".
"I just wish him all the very very best". "So I didn't face one break point, and I didn't feel so much pressure on service games", said Thiem. He is on the verge of another shot at his first ever grand slam title.
"I have had three very nice experiences and seven frightful experiences", said Thiem, who has made the last-eight at a Slam other than Roland Garros for the first time.