Murray won by scores of 7-6 (10), 7-5, 2-6, 3-6, 6-2 at Arthur Ashe Stadium, winning his first Grand Slam while capping off a dream summer.
"Novak is so, so strong. He fights until the end in every single match," Murray said. "I don't know how I managed to come through in the end."
The match lasted 4 hours, 54 minutes, tying the record for longest U.S. Open final. They repeatedly produced fantastic, tales-in-themselves points, lasting 10, 20, 30, even 55 — yes, 55! — strokes, counting the serve. The crowd gave a standing ovation to salute one majestic, 30-stroke point in the fourth set that ended with Murray's forehand winner as Djokovic fell to the court, slamming on his left side.
By the end, Djokovic — who had won eight consecutive five-set matches, including in the semifinals (against Murray) and final (against Rafael Nadal) at the Australian Open in January — was the one looking fragile, trying to catch breathers and doing deep knee bends at the baseline to stretch his aching groin muscles. After getting broken to trail 5-2 in the fifth, Djokovic had his legs massaged by a trainer.
"I really tried my best," Djokovic said.
Just two months ago, the 25-year-old Murray was best known as a player who couldn't quite crack the upper echelon of the men's game.
But he has clearly prospered with coach Ivan Lendl. Like Lendl before him, the Scotsman had lost his first four Grand Slam final appearances, including the Aussie loss to Djokovic early this year.
He is the first British men's player to win a major since Fred Perry did 76 years ago, and he earned $1.9 million US for his effort.
Murray reached the final at Wimbledon, and rebounded from the sting of that loss to Roger Federer to beat the Swiss star in the Olympic gold medal final last month.
Djokovic was looking to win his fifth major since the beginning of 2011. He is now 5-4 lifetime in Grand Slam finals, having lost at the French Open in early June to clay master Nadal.
Murray needed six set points to win the first set of the match delayed a day by adverse weather, taking it 12-10 in a tiebreaker.
It was the longest tiebreaker ever played in the tournament's men's title match, and it lasted 25 minutes.
Djokovic, who had trouble with his footing, was then broken at love in the second game of the second set.
Murray raced to a 4-0 lead, but Djokovic stormed back to threaten to win the set.
He did win the next two despite persistent leg pains, with Murray growing frustrated with his own play.
No one had blown a two-set lead in the U.S. Open title match since 1949, and Murray was determined not to claim that distinction.
Murray broke early to render the fifth set largely without suspense. He needed three championship points before completing his long-awaited Slam.
When Djokovic sent a forehand return long on the final point, Murray crouched and covered his mouth with both hands, as though even he could not believe this moment had actually arrived.
Monday's result represented just the second time in the last 31 Grand Slams, since the 2005 French Open, that the championship trophy was lifted by someone other than Federer, Nadal or Djokovic. The other exception was Juan Martin del Potro's 2009 victory at Flushing.