Murray had broken Djokovic physically at the US Open final and the world No 1 returned the favour to retain his Australian Open title.
The comeback that the 25 year-old Serb was denied at Flushing Meadows in September proved easier to pull off against his contemporary, who failed to drive home the early advantage and went down 6-7 (2-7), 7-6 (7-3), 6-3, 6-3 in a gruelling three hours and 40 minutes.
The four hours it had taken to suppress Roger Federer in the semi-finals weighed heavily on Murray as the match went on as he received treatment for a blistered toe and appeared to be struggling with his hamstring as well.
It was Murray's fifth defeat in six major finals, but the fact that he broke his duck at the US Open last year, after winning Olympic gold, softened the blow of Sunday's result.
"There's going to be some obvious reasons for me feeling a little bit better," said the British number one.
"The last few months have been the best tennis of my life - I made the Wimbledon final, won the Olympics, won the US Open, I was close here as well. It was close.
"I know no one's ever won a Slam, the immediate one after winning their first one. It's not the easiest thing to do and I got extremely close.
"So I have to try and look at the positives of the last few months, and I think I'm going the right direction. This is the first time I've beaten Roger [Federer] in a Slam over five sets. I think I dealt with the situations and the ebbs and flows in that match well.
"I felt much more comfortable on the court today than even I did at the US Open, so that has to be a positive."
So he becomes the latest man to fail to back up his debut Grand Slam by winning his next one, although this is very much the domain of Djokovic, the place where he has been unbeaten since 2010.
Murray will curse his inability to put away the second set, in which he appeared to have the upper hand, with his opponent only just holding for the tiebreak, which he took 7-3, helped by a double fault bizarrely caused by a dropping feather as he served.
That was a decisive passage of play, although a key game was the second one of the second set, when Murray had three break points at 0-40 and failed to put away a relatively straightforward mid court backhand of the kind that he usually devours.
Such slip-ups, at a time when Djokovic was at odds with himself showing real signs of frustration, are the difference when the best players meet each other and are as closely matched as these two.
Djokovic, whose serve was not broken all match despite Murray being such an outstanding returner, got the first break for 5-3 in the third and never looked back as Murray visibly tired.
There were very few opportunities offered to the receiver in the first two sets.
Djokovic had the better chances in the first with five break points split between the sixth and eighth games only for Murray to serve his way out of danger.
The world No 1's frustration at failing to convert, coupled with irritation with his footwear, boiled over in the tie-break as his game capitulated.
It was Murray who was the aggressor in the second as he looked to double his advantage.
He had three chances to leap into a 2-0 lead but Djokovic changed tack, charging the net to escape immediate danger.
It remained on serve until another breaker which was tight until Murray threw in just his third double fault of the tournament at 2-2.
He put his first serve into the net and was shaping up to deliver the second when he noticed a feather dropping on to the court out of the corner of his eye.
Having removed it, he promptly put the second serve long. It was all Djokovic needed to level the match and the momentum appeared to swing further in his favour when
Murray had to call a medical time-out for blisters at the change of ends with television pictures showing the extent of the damage to his right foot.
There was no immediate change in his movement although there was the definite sense the match as now Djokovic's for the taking.
And the top seed needed no second invitation as he set up three break points for a 5-3 lead.
Two poor forehands saw the first two come and go but Murray could not escape a third as Djokovic claimed the first break of the match before serving it out.
Murray was clearly upset at umpire John Blom for not doing more to quieten the crowd and in particular one heckler who had forced him to halt his service action twice at important points of the third set.
Yet he started the fourth on the front foot, setting up his first break point chance since the second game of the second set only for Djokovic to close the door with a booming serve out wide.
By now, Murray was also clutching his left hamstring and it was no surprise that Djokovic broke again for 2-1, winning a long rally at 30-40 after a tired-looking Murray jammed a backhand into the net.
The match was slipping away from Murray and he dropped his serve once more on a double fault as Djokovic established a 4-1 lead.
The effort was certainly there as the world No 3 continued to chase down every ball despite being in obvious discomfort but there was no let-up from Djokovic as he completed his 21st consecutive win in Melbourne and gained revenge for his defeat to Murray in the US Open final last September.
Murray was humble in defeat, and said: 'I want to congratulate Novak, his record here is incredible and he’s the deserved champion.'
Djokovic also credited his adversary, and said: 'It was bad luck for Andy I’m sure we’ll have many more great matches in future. It’s an incredible feeling to win here again. It’s my most successful Grand slam and I love this court.'