It marks the first time Nadal has been the top seed at the New York tournament since 2010. Play begins Monday.
On the women's side, Karolina Pliskova of the Czech Republic is the No. 1 seed. Russian Maria Sharapova is a wild-card entrant and is pitted against second-seeded Simona Halep of Romania in the first round.
Nadal is enjoying a superb season and was placed on the same side of the men's draw as another veteran stalwart in third-seeded Roger Federer of Switzerland.
Scotland's Andy Murray, who is returning from a hip injury, is the No. 2 seed.
Germany's Alexander Zverev, who has won five titles this year, is No. 4. Marin Cilic of Croatia is No. 5, followed by Austrian Dominic Thiem, Bulgaria's Grigor Dimitrov and Frenchman Jo-Wilfried Tsonga.
Neither of last year's finalists are part of the field. Switzerland's Stan Wawrinka, who won the crown, is sidelined with a knee injury, while runner-up Novak Djokovic of Serbia is out with an elbow injury.
Canadian Milos Raonic and Japan's Kei Nishikori are also sidelined with wrist injuries.
Nadal will face Serbian Dusan Lajovic in his first-round match. Murray drew American Tennys Sandgren and Federer meets American Frances Tiafoe.
The women's tournament is viewed as wide open with American star Serena Williams sidelined due to her pregnancy.
Pliskova reached last year's final before falling to Angelique Kerber of Germany. The defending champion is seeded sixth after struggling for much of this year.
Pliskova opens her pursuit of the crown against Magda Linette of Poland.
The match between Halep and Sharapova will be highly anticipated as it represents Sharapova's first appearance in a Grand Slam match since the 2016 Australian Open. Sharapova tested positive for the banned drug Meldonium in Australia and served a 15-month doping suspension.
Sharapova has won five major titles, including the 2006 U.S. Open. She also has won all six previous meetings against Halep.
Third-seeded Garbine Muguruza enters the tournament as one to watch after winning Wimbledon last month -- her second title at the All England Club. The Spaniard squares off against American Varvara Lepchenko in the opening round.
Ukrainian Elina Svitolina, who has won five titles this season, is seeded fourth. Denmark's Caroline Wozniacki is fifth.
Venus Williams is seeded ninth and fellow American Madison Keys is No. 15.
The tournament concludes on Sept. 10.