The world number one had to retire from his fourth-round clash against Stan Wawrinka in New York due to a shoulder injury but encountered few problems as he launched his Japan Open campaign with a 6-4 6-2 triumph.
Djokovic took the fifth break point on offer in the ninth game of the first set before closing out the opener.
Popyrin was never allowed a look at breaking the Djokovic serve and found himself increasingly over-matched as he subsided in an hour and 25 minutes.
Djokovic, 32, will face veteran Japanese wildcard Go Soeda in round two.
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