Djokovic lost out to Rafael Nadal in the final at Flushing Meadows in 2013, going down in four sets to the Spaniard.
Nadal has been forced out of this year's tournament with a wrist injury, and world number one Djokovic will come up against Schwartzman - 79 places below him in the rankings - in his opening contest.
Should the Serbian progress through the opening four rounds, a mouth-watering last-eight clash awaits, with the likes of Andy Murray, Jo-Wilfried Tsonga and home favourite John Isner all in Djokovic's quarter of the draw.
Second seed Roger Federer, who won the tournament five times in succession between 2004 and 2008, begins his campaign against Marinko Matosevic, with the Swiss in line for a possible quarter-final against Grigor Dimitrov.
The Bulgarian is widely tipped to lead the new generation of talent in the game and the 23-year-old begins his search for a first major title in a tie with American Ryan Harrison.
Stanislas Wawrinka, who saw off Nadal in the Australian Open final earlier this year, opens against Jiri Vesely, with fifth seed Milos Raonic also pitted in Wawrinka's quarter.
One notable first-round match sees world number seven Tomas Berdych face 2001 champion Lleyton Hewitt, while David Ferrer - seeded fourth - has been drawn against Damir Dzumhur, the world number 120 from Bosnia-Herzegovina.