On Labor Day in New York, Nadal and Federer progressed to the quarterfinals with ease. Del Potro made a major recovery to come through in five sets, while top seed Karolina Pliskova sped through to meet CoCo Vanderweghe.
Rafa Nadal swept past Aleksandr Dolgopolov in three sets 6-2, 6-4, 6-1 on Monday, as the Spaniard's fine 2017 form continued.
The unseeded Dolgopolov had won two of his last three meetings with Nadal, but couldn't match him this time around.
It was the Spaniard's 50th win at the US Open and he makes the quarterfinals for the seventh time overall, but for the first time since capturing the 2013 title.
The world number one, who returned to the top of the rankings last month for the first time since 2011, will face Russian teen Andrey Rublev after he beat Belgian ninth seed David Goffin.
Rublev won 7-5, 7-6, 6-3 to become the youngest man to reach the US Open quarterfinals since Andy Roddick in 2001.
"Rafa is the real champion and I am going to just try and enjoy it," Rublev said afterwards, who is looking ahead to facing one of his childhood idols.
Argentina's injury-prone Juan del Potro overcame a slow start to beat Austria's Dominic Thiem in five sets 1-6, 2-6, 6-1, 7-6 (7/1), 6-4. He was 2-5 down in the final set before coming back to win.
"I was sick the last two days," del Potro admitted after the match. "I came here trying to play the best I can and then when I see this crowd cheering for me, I was trying to play better every game. I will always remember this." He will play third-seed Roger Federer who needed just three sets to beat Germany's Philipp Kohlschreiber for the 12th time.
The 36-year-old Swiss did not face a break point against Kohlschreiber and the only worry was a medical time-out taken off the court. Federer explained to the crowd: "I needed a rub on my back... or bottom and I didn't want to do it in front of you guys."
Federer has a 16-5 career lead in matches with del Potro but they have split their last six meetings. "It's great to see him back on tour," Federer said. "He's had a rough ride with wrist problems. He's a good guy."
World number one Karolina Pliskova needed just 46 minutes to defeat American Jennifer Brady 6-1, 6-0 and make the US Open quarterfinals.
After facing a match point during her third-round battle against Zhang Shuai on Saturday, Pliskova was never pushed by Brady, who only made 39 percent of her first serves.
"I think she was a little bit nervous," Pliskova said of the 22-year-old Brady during an on-court interview following the match. "It was her first time on Ashe so I tried to take advantage of that."
Next up for Pliskova is 20th-seeded American CoCo Vandeweghe after she beat Czech Lucie Safarova 6-4, 7-6.
The last match of the night saw Madison Keys beat Elina Svitolina in three sets, 7-6(2) 1-6 6-4, to become the fourth US player to reach the quarter finals - along with Venus Williams, CoCo Vandeweghe and Sloane Stephens.