Nadal, back on top of the world rankings for the first time in three years, is a two-time winner in New York, his 2010 and 2013 titles forming part of his 15-Slam portfolio which was embellished by a record 10th French Open in June.
Victory in the men's final on September 10th would also make the 36-year-old the oldest US Open champion of the modern era and oldest overall since Bill Tilden in 1929.
The path to the title for Nadal and Federer has been eased.
World number two Andy Murray, the 2012 champion, withdrew on Saturday after failing to recover from a hip injury.
Two-time winner Novak Djokovic has already shut down his season to recover from an elbow injury while defending champion Stan Wawrinka faces knee surgery.
With Kei Nishikori, the 2014 runner-up, and Milos Raonic also injured, five of the current world top 11 will be missing when the tournament starts on Monday.
However, for tennis romantics, Murray's withdrawal came after the draw was made leaving top seed Nadal and third-seeded Federer in the same half, thereby ruling out a collision in the final.
Nadal, 31, heads to New York on the back of a quarter-final loss to Nick Kyrgios in Cincinnati and a Montreal last-16 defeat to Canadian teenager Denis Shapovalov.
The Spaniard said he would rather not have Federer in his semi-final path, should they get that far.
“I prefer to play against another player, an easier one if it's possible,” said Nadal, who has not got past the fourth round since 2013 and starts his campaign against Dusan Lajovic, the world number 84 from Serbia.
“Finals are more special than semi-finals. But anyway, meeting him here in semi-finals, if that happens that will be something great and amazing.”
Federer, meanwhile, is looking to move beyond Pete Sampras and Jimmy Connors by claiming a sixth US Open and reach a first final in the city since his sensational 2009 loss to Juan Martin del Potro.
His record-blazing eighth Wimbledon title in July was followed by a Montreal final defeat to Alexander Zverev and a pull-out from Cincinnati with a back injury.
But with a 2017 record of five titles, 35 match wins and just three losses, the evergreen Swiss remains the sentimental favourite.
Federer said he would like nothing else than to face Nadal in the semi-finals.
“It would be fun for everybody involved. We have our work cut out there. But, you know, I'd love to play Rafa here in New York,” said Federer, who missed the 2016 US Open to rest a knee injury.
Federer starts his bid for a sixth title against US teenager Frances Tiafoe, the world number 71 who shocked Zverev in Cincinnati.
READ ALSO: Roger Federer, from Mr Angry to Mr Perfect