And Britain's Andy Murray, who opens against Australia's tour bad boy Nick Kyrgios, might have to get past French Open winner Stan Wawrinka and 17-time major winner Roger Federer just to get a crack at Djokovic in the final on the Flushing Meadows hardcourts.
The paths will be filled with qualifiers ahead of Monday's start of the year's final Grand Slam event in New York, where Djokovic's only title came in 2011.
The 28-year-old Serbian star owns nine Grand Slam titles and seeks his third of the year after a third career win at Wimbledon and a fifth trophy at the Australian Open.
Nadal leads Djokovic 22-20 in their all-time rivalry, but Djokovic won their most recent meeting at the French Open quarter-finals.
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Defending champion Marin Cilic, who beat Japan's Kei Nishikori in a final of surprise packets last year, likes Djokovic to claim the crown once again this time.
"I would still put Novak at the top of the list, even though Andy has shown his tennis has gone up and he is motivated," Croatian ninth seed Cilic said.
"And I hope there are a few guys lower in the draw who are going to make it interesting.