World number one Nadal, the 2010 and 2013 champion, brushed aside Russian 19-year-old Rublev 6-1, 6-2, 6-2 in just 97 minutes.
The women’s semi-finals will be an all-American affair for the first time since 1981 after CoCo Vandeweghe and Madison Keys set-up a last-four duel.
Thursday’s other tie will see seven-time major champion Venus Williams face Sloane Stephens.
“It would be more special if Roger and I met in the final this year, so we will have to try and come back and make it happen,” said 31-year-old Nadal, who has reached his 26th Grand Slam semi-final.
The reigning French Open champion added that he might not watch all of the Federer-Del Potro match as it clashes with his dinner time.
“We are from Spain and we always eat very late but of course I will be paying attention to it,” Nadal said.
Rublev, bidding to be the youngest man in 17 years to reach the semi-finals, had no complaints over his loss.
“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.
Federer faces Del Potro for the first time in New York since the Argentine star rallied from a set and a break down to shock him in the 2009 final.
That thrilling five-set triumph ended Federer’s five-year reign as champion and his 40-match win streak.
Del Potro had also crushed Nadal in straight sets in the semi-finals.
Del Potro, who saved two match points to defeat sixth seed Dominic Thiem in a fourth-round thriller on Monday, has been plagued by injury ever since his moment in the New York spotlight eight years ago.
He has undergone four wrist surgeries, missed 10 Grand Slams and, at one stage last year, his world ranking slumped to 1,045.
If Nadal and Federer, the Australian Open and Wimbledon champion, do meet on Friday, it will also be a duel for the world number one spot.
– All American -Vandeweghe reached the semi-finals, knocking Karolina Pliskova off her world number one perch.
American 20th seed Vandeweghe claimed a 7-6 (7/4), 6-3 win over the Czech Republic’s Pliskova, whose brief eight-week stay as world number one ends with Wimbledon champion Garbine Muguruza taking over.
Vandeweghe’s victory means that the US Open will have an all-American semi-final line-up for the first time since 1981 after Keys defeated Estonian qualifier Kaia Kanepi 6-3, 6-3.
“I won the juniors here when I was 16 and dreamed of playing on the real stage,” said 25-year-old Vandeweghe, who also made the semi-finals at the Australian Open, beating then-world number one Angelique Kerber in the process.
The last time four US women were in the semis was 36 years ago when eventual champion Tracy Austin, Chris Evert, Martina Navratilova and Barbara Potter all made it.
Pliskova, who had to save a match point to beat China’s Zhang Shuai in the second round, shrugged off losing her top spot.
“I just don’t care,” she said. “I didn’t choose to be at this position where I am now. There are many more Grand Slams to come. I believe I can win one.”
Keys, the 15th seed, will be playing in her second Slam semi-final after the 2015 Australian Open.
“It means the world to me,” said Keys who underwent wrist surgery earlier this season.
“If someone had said after Wimbledon I would be here now I wouldn’t have believed them.”
Kanepi, ranked 418 but a six-time quarter-finalist at the Slams, had battled back from crippling foot injuries and a debilitating virus that has limited her to just five events in 2017.
She was unable to convert three break points in the third game of the opening set and there was no way back. DM
There is a video game called Lose/lose where the player has a random file deleted every time they kill an enemy.