Djokovic becomes just the third man to win the tournament three times or more even though he was at times a distance from his best.
Murray was similarly below par as Djokovic raced through the first set, but took the world number one all the way in the second - though a total of one break point in the entire match for the Scot told its own story.
Djokovic's victory was his third at Miami and avenged his 2009 loss to Murray here at Crandon Park.
"I thought I played a great match from the start to the end," Djokovic, who did not drop a set throughout the tournament, said.
"But with such a quality player you really never know, that's why he's right at the top. He always comes back even if you feel that you have control of the match so I am really happy to close it out in straight sets."
Murray signalled early intent in the first game as he hit a perfect top spin lob over the Serb that landed on the line, but the world number one replied with a lob of his own a game later.
In the fourth game Djokovic struck with a touch of brilliance: he recovered from 40-0 down to draw level, hitting some brutal winners in the process. The game went to five deuces, but eventually the Serb's pressure told as he forced Murray to hit wide.
Murray was winning only 47% of his first serves and Djokovic opened up a sizeable lead as he broke the Murray serve again. He took the opening set with consummate ease with a couple of winners and a crashing ace to round it off.
Immediately in the second set though, the Serb showed signs of tiredness in the heat. He set up two break points in the third game, but reeled off a succession off errors and was the first to crack after a marathon 22 shot rally with a forehand low into the net as he failed to move his feet.
Murray was failing to make any inroads on the Serb's serve, and was continuing to struggle on his own. Neither player could get the crucial break, though Djokovic had ample chances to do so.
In the 11th game Murray benefited from a touch of fortune: he put his hand up to challenge a call, yet the umpire failed to see and Murray went on to win the rally at deuce and on to hold the game.
The match continued to excite, yet the lack of quality was there to see as both players hit twice as many errors as winners. Djokovic showed great depths of belief to bring the set to a tie break, though, and there were fleeting moments of world class quality.
The point of the match came in the tie break as Murray hit an astonishing drop shot off a vicious Djokovic slice that gave him brief hope, but Djokovic led from the first point and took the match with relative ease to defend his title.