While the two have shared some of modern tennis' most titanic battles, Nadal and Federer have never met at Flushing Meadows – but a semi-final meeting between the two rivals now beckons should both men reach the final four.
Number one seed Nadal will begin his campaign against Serbia's Dusan Lajovic while third seed Federer will take on 19-year-old American Frances Tiafoe in his opening match.
Murray, knocked off top spot in the men's ATP rankings by Nadal last week, will be back in action for the first time since his quarter-final defeat to Sam Querrey at Wimbledon, where he struggled with a hip injury.
Maria Sharapova returns for her first grand slam match in 19 months in New York but has been paired with number two seed Simona Halep. British number one Johanna Konta will begin her campaign against Aleksandra Krunic of Serbia, who is ranked 77th in the world.
Defending champion Angelique Kerber takes on Japan's Naomi Osaka of Japan.
The final grand slam of 2017 will be marked by a number of notable absentees, including former world number one Novak Djokovic, who will sit out for the remainder of the year to recover from an elbow injury that has plagued him for the last 18 months.
Defending champion Stanislas Wawrinka, who beat Djokovic in last year's final, is out for the remainder of the season to undergo knee surgery, while six-time champion Serena Williams will miss this year's tournament to have her first child.