The Scot - seeded eighth for the tournament - takes on the world number one in the second match on Arthur Ashe court, and you can follow LIVE coverage throughout right here.
And he told the BBC that despite the fearsome prospect that awaits him against a player in blistering form this summer, he can't wait to get going.
"Playing at night against the number one player in the world is exciting," said the 27-year-old.
"If you aren't getting motivated or pumped for those matches, then that's when there's a problem.
"That's what you put the work in for, so that when you come to these events and you do have to play against the best players, you're ready.
"And as much as it's incredibly tough and challenging - that's what you enjoy."
[MATCH PREVIEW: Murray and Djokovic set for quarter-final epic]
Djokovic has won four of the last five meetings between the pair - with Murray beating his long-time friend and rival only in the 2013 Wimbledon final in recent times. That victory remains Murray's last tournament win.
But the Scot has the advantage of having beaten the Serb in their only previous encounter at Flushing Meadows: the 2012 US Open final, which Murray clinched in five sets after letting a two-set lead slip.
The fact that the two play so often - this will be their 21st encounter as professionals - means that tactics and mind games will be as important as anything else.
"I would say we play a fairly similar style," said Murray.
"I think that's why a lot of the matches have been long games, long rallies, long points, because we do a lot of the same things well.
"I don't know exactly what I'm going to do, but by the time I get on the court I'll have a good idea."
Murray's Amelie Mauresmo believes Murray can pull off a shock victory if he plays at his best.
"I think he should really go out there and express fully what he's capable of doing," Mauresmo told the BBC.
"The pressure is probably a little bit more on Novak, which is normal, he won Wimbledon."
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