The reigning title holder started his Roland Garros campaign with a 6-3, 6-4, 6-2 win over Marcel Granollers.
Novak won his first French Open title in 2016 and completed career Grand Slam beating Andy Murray in the final (3-6, 6-1, 6-2, 6-4).
The defending champion passed a tough first-round assignment with a 6-1, 7-6, 6-2 victory over Spaniard Fernando Verdasco (ATP #40).
Top seed and defending champion will open campaign in his 12th US Open appearance against Jerzy Janowicz (Poland).
The 2016 US Open draw will be led by reigning champion Novak, followed by Olympic gold medalist Murray, Wawrinka and Nadal.
Nole captured his 30th straight Grand Slam win beating Frenchman Adrian Mannarino 6-4, 6-3, 7-6 (5).
The top seed opened his Wimbledon title defence campaign with a straight-sets victory over British wildcard James Ward.
Gentlemen’s singles draw has been made for Wimbledon, the most prestigious tennis tournament in the world (June 27 – July 10).
After capturing his first Roland Garros title on Sunday, Nole has set new ATP ranking record.
Novak beat Andy Murray 3-6, 6-1, 6-2, 6-4 to complete the career Grand Slam, and became just the eighth man to accomplish the feat.