The Scotsman at last won a major after losing four Grand Slam finals by battling it out in blustery conditions at Arthur Ashe Stadium 7-6, 7-5, 2-6, 3-6, 6-2, here at Flushing Meadows Monday.
It looked as if Murray had the measure of the windy conditions as he took the first two sets before Djokovic came back roaring to take the next two.
The Briton quickly regained his equanimity in the deciding set and jumped into a 3-0 lead pulling on his reserve stamina by breaking the Serb's serve twice. Then and there the Serb's fight was over and the Briton raced to take the set and the match.
Djokovic thus failed to become the first to defend the title at the US Open since the five straight wins by Federer (2004-2008), reports Xinhua.
Andy Murray poses with the US Open title. Photo: AFP
The last British male champion to win a Grand Slam title was Fred Perry, who claimed the US Open in 1936.
Murray, 25, had an extra day's rest than his opponent as Djokovic's semifinal against David Ferrer was postponed to Sunday.
The Serb had to play two matches in two days and that gave Murray the edge over the defending champion, especially in the fifth set.
The defeat cost Djokovic heavy. Had he won he would have collected $2.9 million payout instead of the $1.45 million runner-up cheque as he would have pocketed $1 million bonus for leading the US Open series.
Murray earned $1.9 million, bringing his career prize money to more than $23 million.
Djokovic, 25, was the 2-5 favorite at the Las Vegas Hotel's Super Book, translating to a 71 percent probability of a sixth major title. A successful $100 dollars bet on underdog Murray yielded a 210-dollar profit.
The win also broke a stranglehold on major titles by Roger Federer, Rafael Nadal and Djokovic, who combined to win 29 of the previous 30. Juan Martin Del Potro's 2009 US Open victory was the lone exception.
Murray's breakthrough came in his 28th Grand Slam event and after losing four finals. He lost the 2011 Australian Open final to Djokovic and was beaten by Federer in three others -- at the 2008 U.S. Open, in Australia in 2010 and this year at Wimbledon.
There were four service breaks in the first eight games of the opening set as the players tried to adjust to the swirling 26 kph wind.
Playing tentatively instead of going for winners, the two men exchanged 54 strokes on one point in the sixth game of the 87-minute set. The tie-breaker lasted 24 minutes.
After Murray won the first-set tie-breaker on his sixth set point, he took a 4-0 lead in the second set by breaking Djokovic's serve twice.
Novak Djokovic congratulates Andy Murray after his victory. Photo: AFP
Djokovic stormed back to win five of the next six games, only to have Murray break his serve again in the 12th game to win the set.
Djokovic rallied to clinch the next two sets to stay alive and revive hopes of defending the title. But Murray repeated what he did in the second set by breaking the Serb's first two service games, establishing a 3-0 lead.
Though Djokovic broke one back in the fourth game, but could not hold off the sliding and was broken for the ninth time in the match in the seventh game to lose.
With the win, Murray, who took the gold medal at the London Games in July, also became the first man to win both a gold medal and the US Open title since tennis returned to the Olympics in 1988.
Murray called the three-set Olympic gold medal-winning victory against Federer "the biggest win of my life."
Now Murray has a Grand Slam as well, moving past Nadal to become the ATP World Tour's third-ranked player.