The Briton had lost his last six matches against the world number one and it was going against him again when he dropped the opening set at Crandon Park on a tie-break.
Third seed Murray battled back valiantly to snatch the second set and take the match into a decider, only for his game to desert him as Djokovic claimed a 7-6 (7/3) 4-6 6-0 victory after almost three hours on court.
It proved a disappointing climax to an enthralling match, with Murray broken again before Djokovic served out successfully for his fifth Miami title.
It was a second defeat to Djokovic in as many weeks for Murray, who was also beaten by the Australian Open champion at straight sets in Indian Wells.
However, although he admitted tiredness got the better of him on this occasion, the Scot is confident he is catching up on his rival.
He said in the post-match presentation: “It’s been a good start to the year for me and I’ve made progress from where I was at this stage last year.
“I’m not quite there with Novak yet but I feel like I’m getting a little bit closer. I just need to keep working hard and hopefully that will come.
“I’m sorry I couldn’t make more of a fight of it in the third set. I was trying but my legs were tired and I couldn’t quite finish hard enough.
“But Miami is a very special place for me, I always enjoy coming back so I’m sorry I couldn’t quite get the job done in the final but I’ll be back next year and try one more time.”
Djokovic also spoke of the enjoyment he got from playing in Miami, saying: “This is truly one of the better tournaments on the tour that we have. The best players in the world are participating in this event and it’s truly a very special place for tennis.
“Hopefully we’re going to have many more great years to come.”