The Scotsman, beaten in his four previous grand slam finals, he won the fifth time with a nerve-jangling victory at a windy Arthur Ashe stadium where the players had to battle the elements as much as each other.
With both struggling to control the ball in the gusting winds and battling exhaustion after the equal-longest final ever played at the US Open, the match became a test of courage and stamina and it was Murray who handled the decisive moments better.
After losing the first two sets, Djokovic suddenly raised his game, winning the next two to force a deciding fifth set and seize the momentum as Murray started to wilt.
But the Olympic champion regained his composure when it really mattered, jumping to a 3-0 lead in the final set with two service breaks then hanging on to seal victory.
He provided Britain with their first male champion at a major since Fred Perry won the 1936 US Open.
Reporting by Julian Linden; Editing by Ian Ransom