Millman dragged Djokovic into long, searching rallies and four-time US Open champion John McEnroe said the Australian's level of play was "similar" to the standard at which he played in his memorable fourth-round win.
The 31-year-old Serbian, whose Wimbledon victory in July was his first Grand Slam success in more than two years, won 6-3, 6-4, 6-4 against the world number 55 in stifling conditions at Flushing Meadows.
The common thread among almost all the U.S. Open matches this year is the excessive heat and humidity at Arthur Ashe Stadium in NY. Djokovic looked exhausted after a 60-minute first set, but was given a brief break as Millman requested a change of clothes due to the extreme humidity.
She has made it to the final four at three of the past five Grand Slam tournaments but is still seeking her first major championship.
'But I watched the second part of the match, and, I mean, Roger was not playing well.
The Australian also suffered with the heat, having to disappear off court at 2-2 in the second set to change his sweat-soaked kit.
It was an impressive effort on Millman's part, but it's nothing Djokovic isn't used to.
Upon missing a gimme volley - after Millman retrieved a lob with some incredibly scrambling - and then pushing a return wide, Djokovic staggered back into position before tipping water over his head at the changeover.
Both players were clearly struggling in the extreme heat and Djokovic admitted after that this has been the toughest US Open in the last decade.
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"I think when I cracked the top 50, I cracked the top 50 for like a week a few weeks ago", he said.
"I'm really, really proud - not proud but happy - with how my body has held in there and physically I actually feel pretty good in this caper", Millman said.
The Wimbledon 2018 champion Novak Djokovic has not lost a set since the round of 64.
Djokovic, grateful for a bit of a breather, sat grinning in his chair with his shirt off, much to the crowd's amusement.
It was a very unusual match, with Djokovic nearly losing his cool after receiving two warnings for time violations, ultimately losing a game for it.
"I was, alongside many other people, anticipating the match against Federer", Djokovic said. "He doesn't miss a lot himself".
"I don't think that's a normal occurrence", John Isner said on Tuesday after his quarterfinal loss to Juan Martin del Potro. He fended off seven break points but couldn't stop Djokovic from converting on the eighth to take the two-sets to one lead.
After reaching his 11th semi-final in New York, Djokovic will face Kei Nishikori on Friday. Naomi Osaka won her quarterfinal in the match that preceded Nishikori's.
"I don't know why but it's always a battle with Marin", said Nishikori, who stretched his career record over the seventh-seeded Croatian to 9-6.