In the 12th meeting between two veterans of the sport, and seven years after their last one, 19th seed Dimitrov registered only his fourth win over the Scot.
Murray wilted inside the Arthur Ashe Stadium, the court upon which he won his first Grand Slam title in 2012, as he slipped to a 6-3 6-4 6-1 defeat.
A ding-dong of a first set, including two brutal 15-minute games, was poised at 3-3 with almost an hour played and the match was shaping up to be another Murray marathon.
Murray had lost eight points in a row to slip behind but hit back after an astonishing get from a 36-year-old with a metal hip, retrieving a net cord by deftly angling the ball away from Dimitrov. He continued his run past the net post and into Dimitrov’s side of the court, where the Bulgarian clapped his opponent before both tapped rackets.
That was where the niceties ended, though, and Murray’s hopes quickly went south. He came up with a shocking service game, two double-faults and two unforced errors gifting Dimitrov the set and the momentum.
Murray was broken again at the start of the second and his shoulders slumped even further when his solitary chance to break back drifted wide.
The constant chuntering to his team was getting less and less cordial and, at 4-1 down in the third, he gestured to them that the match was over as a contest.
The former world number one was proved to be right two games later as another attempt to challenge in the later rounds of a Grand Slam fell well short.