The Serbian world number one always looked to have the upper-hand in what was a hard-fought 7-6 (7-1) 6-7 (1-7) 6-2 6-4 victory at Flushing Meadows on Wednesday.
Murray, the British eighth seed, was hanging on until 18 unforced errors in the fourth set cost him in the quarter-final.
Djokovic, who will face Japanese 10th seed Kei Nishikori in the last four, finished with 46 winners and 48 unforced errors.
Murray ended up committing 65 unforced errors and will finish the year without a grand slam.
Only one of Djokovic's seven grand slams have come at the US Open, but he has reached the last four every year from 2007 onwards.
The pair traded multiple breaks in the first two sets of an entertaining contest, highlighted by several long rallies.
But Murray struggled in the first-set tie-break and Djokovic in the second, leading to the encounter being square after two hours 13 minutes.
Murray was unable to maintain his level and he was battling regularly on his service games.
Djokovic eventually went on to complete his victory by breaking Murray to 15 in the 10th and final game of the fourth set.