Murray prevailed 6-4, 4-6, 6-3 to end an eight-match hoodoo, dating back to his success over the Serbian in the 2013 Wimbledon final, to secure his fourth title of the year.
The 28-year-old broke his rival in the second game of the third set and surged into a commanding 3-0 lead before saving seven break points in the fifth to maintain his break advantage at 4-1.
Victory also represented Murray’s first against Djokovic, who was chasing a 25th Masters title, in a three-set Masters match that went the distance, while it was his first win against him on a hard court since the 2012 US Open final.
By virtue of reaching the final by overpowering Japan’s Kei Nishikori in their last-four clash, Murray had already ensured that he will overtake Roger Federer and return to No2 in the ATP rankings for the first time since 2013.
Murray will bid to claim his second US Open crown at Flushing Meadows when the tournament gets underway on 31 August.