Nadal, meanwhile, also wasted little time in seeing over Ivan Dodig, 6-4, 6-3, 6-3, to stretch a career-best hardcourt win streak to 18 matches.
Federer and Nadal have met 31 times before but never at Flushing Meadows, and it would be a mouth-watering encounter.
First Federer must beat his old junior rival Tommy Robredo, who ended the run of British qualifier Dan Evans in a tough four-setter, while Nadal, who has won nine titles since returning in February from a seven-month injury layoff, meets German Philipp Kohlschreiber.
Federer said: “I only start really focusing on it once I’m really right there, like the moment I would win my next round and he did the same.
“But as long as it’s not the case, I’m really focused on making sure that from my side I do things the right way and professional.
“I don’t look ahead, even though I understand the urge of the press to try to go there already, which is entirely normal. I have gone through that my entire career, people talking about our matches even before the tournament started.
“We’re used to it. We know how to handle it. Clearly I think we both hope it’s going to happen this time for the first time in New York.”
Nadal, who has not lost his serve in three matches, believes he will have to improve should he meet Federer, despite connectubg on 65 per cent of his first serves and fired 37 winners in improving to 56-3 this year.
“I have to improve a little bit of everything to keep going in the second week,” Nadal said. “To win matches, if you are not playing your best, it’s impossible.”
Spanish fourth seed David Ferrer, projected to face either Federer or Nadal in the last four, outlasted Russian-born Kazakh qualifier Mikhail Kukushkin 6-4, 6-3, 4-6, 6-4 to reach the last 16, where he will meet either 18th-seeded Serb Janko Tipsarevic or American Jack Sock.
Ladies draw
Elsewhere, Victoria Azarenka escaped an upset bid while Daniela Hantuchova saved four match points, but Grand Slam winners Petra Kvitova and Svetlana Kuznetsova were ousted.
Belarus second seed Azarenka, who lost to top seed Serena Williams in last year’s final, outlasted French 26th seed Alize Cornet 6-7 (2/7), 6-3, 6-2.
Next up for Azarenka will be Serbian 13th seed Ana Ivanovic, the 2008 French Open champion who rallied past American Christina McHale 4-6, 7-5, 6-4.
Czech seventh seed Kvitova, the 2011 Wimbledon champion who was diagnosed with a virus on Friday, made 27 unforced errors and seven double faults in losing to 81st-ranked US wildcard Alison Riske 6-3, 6-0.
Russian 27th seed Kuznetsova, the 2004 US Open and 2009 French Open champion, made 35 unforced errors in losing 7-5, 6-1 to Italy’s 83rd-ranked Flavia Pennetta.
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