If Djokovic and Nadal meet in the semi-final, it'll be their 50th match against each other, with the former leading the rivalry 26-23. Photograph: (Getty)
3rd seed Wawrinka will potentially meet Olympic champ Murray in the other semi-final. Serena will look to win a modern-era record 23rd Slam
Defending champion Novak Djokovic and two-time winner Rafel Nadal have been pitted in the same half of the draw, while number three seed Stanislas Wawrinka will potentially meet Olympic champion Andy Murray in the other semi-final.
In the women's draw, world number one Serena Williams will be chasing history as she looks to win a modern-era record 23rd Grand Slam.
Djokovic will be first up against the big-serving Jerzy Janowicz of Poland, a Wimbledon semi-finalist in 2013.
One of the most-viewed matches of round one at Flushing Meadows will be Murray's encounter with Lukas Rosol. The duo has had an acrimonious relationship, having been involved in an ill-tempered match in Munich last year.
Fourth seed Nadal will open his campaign against Denis Istomin of Uzbekistan.
Roger Federer's withdrawal from the event means that Wawrinka is seeded third in the competition. But the draw looks tricky on paper as he has to first dodge Spain's Fernando Verdasco and then clash with sport's bad boy Nick Kyrgios in the round of 16.
Wawrinka would then potentially face the resurgent Juan Martin del Potro, who incidentally knocked him out of Wimbledon this year.
Thirty four-year-old Serena's opening match will be against experienced campaigner Ekaterina Makarova of Russia, a former US Open semi-finalist.
Second seed Angelique Kerber, the Australian Open champion, starts against Slovenia's Polona Hercog.
Third seed Garbine Muguruza of Spain, the reigning French Open champion, and fourth-seeded Agnieszka Radwanska of Poland start against qualifiers.
(WION with inputs from agencies)