The Serbian, looking to end the year on a high in terms of majors, saw off Rogerio Dutra da Silva in straight sets on Arthur Ashe, beating the unheralded Brazilian 6-2 6-1 6-2.
It was far from a vintage performance from the 25-year-old, who converted just six of the 16 break points that came his way, but he was never in trouble against an opponent who made 36 unforced efforts.
Djokovic was not flawless in that department either, giving away 19 points, but his 29 winners helped him over the line.
By winning, he also ensured he maintained his record of having never lost to a player ranked outside the top 100 at a grand slam tournament.
The Serb said: "It was different conditions today [Friday] obviously from the first match I played. I didn't know much about my opponent, I'd never seen him play.
"So that could have been a difficulty at the start in order to figure out what his game plan is. But I played well from the start to the end.
"Obviously I want to spend as little time as possible on the court. I have played a lot of tennis, a lot of matches, through the course of this summer.
"I had also two long weeks on hard courts in Toronto and Cincinnati, so the lack of matches is not something that is worrying me. Actually, I just want to focus and try to win in straight sets every match that I play."
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Djokovic also gave his reaction to Andy Roddick's announcement yesterday [Thursday] that he will retire after the tournament, praising the 30-year-old's contribution to the sport.
"Andy's situation just shows how quickly everything can turn around," said Djokovic. "But I listened to his press conference yesterday, I admire his career.
"He was one of the greatest competitors around, probably the biggest server ever. I'm sure that he's proud of his career, and all American tennis should be.
"I guess he felt that it's time for him to move on, to stop playing tennis, and to do something else.
"The great thing that he said yesterday [Thursday] is that he wants to continue on his legacy of playing tennis and try to transfer that knowledge to somebody that is coming up and that needs help from such a champion.
"So that's great. You want to share the love for the sport and your knowledge and experiences with somebody else that wants to become like you."