Federer has never faced Spanish legend Nadal on the New York hardcourts in the year's final Grand Slam tournament.
World number one Rafael Nadal could face third-ranked Roger Federer in the semi-finals of the US Open under the draw unveiled Friday.
Swiss star Federer, a 19-time Grand Slam champion who won this year's Wimbledon and Australian Open titles, has never faced Spanish legend Nadal on the New York hardcourts in the year's final Grand Slam tournament.
Nadal, a 15-time major champion who this year won his 10th French Open title, owns a 23-14 edge in his career rivalry with Federer, but the Swiss has won their past four meetings, including at this year's Australian Open final.
Nadal begins his quest for a third US Open crown after 2010 and 2013 against Serbian Dusan Lajovic. He could face Frenchman Richard Gasquet in the third round, a foe he has defeated in all 15 of their previous meetings.
The 31-year-old Spaniard could meet Czech Tomas Berdych in the fourth round and Bulgarian seventh seed Grigor Dimitrov in the quarter-finals.
Federer, 36, opens his run in the Flushing Meadows fortnight against American Frances Tiafoe and could meet Australian Nick Kyrgios in the fourth round as well as Austrian seventh seed Dominic Thiem in the quarter-finals.
Tiafoe upset Germany's Alexander Zverev in the second round at Cincinnati last week.
British second seed Andy Murray plays American Tennys Sandgren in his first match with French 16th seed Lucas Pouille a possible round of 16 opponent and French eighth seed Jo-Wilfried Tsonga potentially awaiting him in the quarter-finals.
Tsonga's first match will be against Romanian Marius Copil.
Fourth seed Zverev and Croatian fifth seed Marin Cilic are also possible last-eight opponents.
Zverev opens against a qualifier while Cilic begins against Frenchman Gilles Simon.
Zverev could face South African Kevin Anderson, whom he beat earlier this month in the Washington final, in the third round and US 13th seed Jack Sock in the fourth round.
Cilic, the 2014 US Open winner, could meet US 10th seed John Isner in the last 16.
Argentina's Juan Martin del Potro, the 2009 US Open champion, is a potential fourth-round opponent for Thiem.
Dimitrov's fourth-round foe could be Belgian ninth seed David Goffin or French 18th seed Gael Monfils.
The field is missing several top contenders due to injury, including defending champion Stan Wawrinka of Switzerland, two-time US Open winner Novak Djokovic of Serbia, Japan's Kei Nishikori, the 2014 runner-up, and Canada's Milos Raonic.