Serbian World No.1 Novak Djokovic will take on Brazilian Joao Souza in the first round of US Open and could face Spain's Rafael Nadal in the quarterfinals, according to the tournament draw released on Thursday.
Second-ranked Swiss Roger Federer will kick off his quest for a record sixth title against Argentina's Leonardo Mayer.
Barring one or more upsets, Djokovic would square off in the tournament's final eight against Nadal, a former No.1 and two-time US Open champion who must get past promising Croatian teenager Borna Coric in his opening match.
The draw puts Djokovic on course for a possible semi-final rematch against fourth-seeded Kei Nishikori of Japan, who upset the Serbian in last year's semi-finals.
Nadal missed last year's US Open due to a wrist injury and comes into this year's event with low expectations after winning just two of nine matches thus far in 2015 against top 10 players.
Federer is expected to meet sixth-seeded Czech Tomas Berdych in the quarters prior to a potential showdown in the semi-finals against Britain's Andy Murray, who has a difficult draw that includes a first-round match-up against talented Australian 20-year-old Nick Kyrgios and a possible quarter-final clash versus talented Swiss No.5 seed Stanislas Wawrinka.
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Defending champion Marin Cilic of Croatia is seeded ninth and could face Spanish No.7 seed David Ferrer in the round of 16 and then Nishikori in the quarters.
The biggest story of the US Open, however, is American three-time defending champion Serena Williams' bid to become only the sixth player in tennis history - after Don Budge, Maureen Connolly, Rod Laver, Margaret Court and Steffi Graf - to win all four Grand Slam singles titles in the same calendar year.
Serena, the winner of 21 Grand Slam singles titles will kick off that quest by taking on Russia's Vitalia Diatchenko in the first round and could later face countrywoman Sloane Stephens - who stunned Williams in the 2013 Australian Open - in the third round and Russian No.3 seed Maria Sharapova in the semi-finals.