South African 15th seed Kevin Anderson stunned the British third seed 7-6 (7/5), 6-3, 6-7 (2/7), 7-6 (7/0) to reach his first Grand Slam quarter-final after seven prior fourth-round defeats.
"It was the match of my life," Anderson said on Monday. "This is a great accomplishment for me."
Not since a third-round exit in the 2010 US Open had Murray been eliminated so early at a Grand Slam tournament.
"That's obviously something that is disappointing to lose because of that. That's many years' work that's gone into building that sort of consistency. To lose that is tough," said Murray, the 2012 champion.
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Anderson, 1-5 in prior matches against Murray, fired 25 aces in ending an 0-15 career hoodoo against top-10 opponents and his fourth-round hex to book a last-eight date with Swiss fifth seed Stan Wawrinka, the reigning French Open champion.
"I'm just so excited to be through," said Anderson. "Beating a guy like Andy, I really feel like I've taken a step forward. It's amazing. I feel like it's a great accomplishment."
He dropped his first set of the tournament but reached an eighth quarter-final in his past nine Grand Slams, denying 68th-ranked Young his first Slam quarter-final.
Anderson is the first South African in New York's last 16 since Wayne Ferreira in 2002.
He came in off a third career title at Winston-Salem.
With New York City FC and former England midfielder Frank Lampard watching from the player's box, Murray fell behind two sets and a break, roared back, but ultimately could not win the tension-packed encounter at Louis Armstrong Stadium.
Murray had 49 winners and 20 unforced errors, but did not make a forehand winner until the last game of the second set. Anderson blasted 81 winners to 57 unforced errors.
Anderson ripped a forehand winner on the final point of the opening tie-break to take the set after 69 minutes, then broke Murray's first service game of the second set on the way to a 5-1 edge.