The Scotsman, beaten in his four previous Grand Slam finals, made it fifth time lucky on Monday with a nerve-jangling 7-6 7-5 2-6 3-6 6-2 victory at a windy Arthur Ashe Stadium where the players had to battle the elements as much as each other.
With both men struggling to control the ball in the gusting winds, and battling exhaustion in a slugfest that tied the record as the longest final at Flushing Meadows, Murray emerged triumphant over the defending champion, proving he belongs among the game's elite.
"I proved that I can win the Grand Slams," Murray said.
"And I proved that I can last four and a half hours and come out on top against one of the physically strongest guys that tennis had probably seen, especially on this surface.
"(I learned) to not doubt myself physically and mentally from now on. I'm sure that will have a positive impact in the future."
After losing the first two sets, Djokovic suddenly raised his game to win the next two and force a deciding fifth set, seizing the momentum as Murray started to wilt.
But as Murray's supporters, including actor Sean Connery and Manchester United manager Alex Ferguson, shifted uneasily in their seats, the Olympic champion regained his composure and jumped out to a 3-0 lead in the final set before hanging on to seal an emotional victory.
"It was an incredibly tough match and obviously it felt great at the end," Murray said, adding that the word "relief" was foremost in his mind.
"I'm very happy that I managed to come through because if I had lost this one from two sets up, that would have been a tough one to take."
The 25-year-old, a survivor of the 1996 Dunblane school massacre, won a titanic first set that took almost an hour and a half to complete and ended in a 22-point tiebreaker, then added the second despite blowing a 4-0 lead.
Djokovic, already a five-time Grand Slam champion, rebounded to win the third set, then took the fourth to raise the prospect of becoming the first man since Pancho Gonzales in 1949 to win the final after losing the first two sets.
However, the world number two was unable to conjure another fightback as his legs started to cramp and Murray wrapped up victory after four hours and 54 minutes, the same time it took Mats Wilander to beat Murray's coach Ivan Lendl in the 1988 final.
"If I won that first set and had some chances maybe the match would go a different way," said Djokovic, who asked for a medical timeout to treat a groin strain just as Murray was about to serve for the title.
"But there is no reason to go back and say: 'What if? What if?'
"I had a great opponent today. He deserved to win this Grand Slam more than anybody."
Before Murray's triumph, the last British man to win a major was Fred Perry, who clinched his final Grand Slam in New York in 1936, the same year Britain's King Edward VIII abdicated to marry American socialite Wallis Simpson.
Murray emerged as the man most likely to end that barren run when he made it to the 2008 U.S. Open final, losing to Roger Federer in straight sets. He then made the Australian Open final in 2010 and again in 2011 but doubts about his mental toughness grew when he lost them both in straight sets.
The turning point came just a few months ago.
He made the final at Wimbledon and although he lost to Federer he won the first set and with a bit of luck, might have won the match.
A few weeks later, he avenged that loss by beating Federer in the Olympic final and now has a Grand Slam to go with his gold medal.
"When I was serving for the match, it's something that I realised how important that moment was for British tennis or British sport," Murray said.
"It's something that hasn't happened for a long time obviously in our country so I'm obviously proud that I managed to achieve it."