Murray defeated Djokovic 7-6 (10), 7-5, 2-6, 3-6, 6-2, in a match that featured an opening set that lasted 1 1/2 hours.
That last man from Great Britain to win a Grand Slam title was Fred Perry, who won the U.S. Open 76 years ago.
Both players had trouble with the conditions on Arthur Ashe Court, with shots wither being carried long or stopped short by the strong winds.
“When the conditions have been like they have been, you need to focus so hard,” said Murray. “On almost every shot because you know the ball is very hard to control.”
Murray said he didn’t think about the long victory drought for British tennis until he was serving for the match.
“When you're on the court, you don't necessarily feel it, but I know when I was serving for the match, there's a sense of how, big a moment that is in British tennis history,” he said.
It looked like Djokovich was going to make an early exit after he feel behind 4-0 in the second set. While he would eventually lose the second, he rallied back and used the momentum to take the next two sets.
“Any loss is a bad loss, there is no question about it,” said Djokovich. “I'm disappointed to lose the match, but in the back of my mind I knew that I gave it all. I really, really tried to fight my way back through.”
This is the first Grand Slam for Murray in his fifth time in a Grand Slam final, including losing a heartbreaker to Roger Federer at Wimbledon earlier this summer.
Murray said he didn’t let himself think about those defeats going into the fifth set.
“I wasn't thinking about the other finals,” he said. “I was thinking a bit more about what happened the last couple of sets and the situation I kind of found myself in after I guess it was nearly four hours of play by that stage.
“I went to the toilet after the fourth set and just had a think and, you know, said, ‘it's just one more set, give everything,’” he added. “You don't want to come off this court with any regrets.”