He netted a service return, and Millman converted his second set point to seize a two sets to one lead.
Unseeded John Millman produced the performance of his career to end Roger Federer's interest in the 2018 US Open with a stunning 3-6, 7-5, 7-6 (7), 7-6 (3) victory in the small hours at Flushing Meadows.
Following an injury interrupted campaign in 2017, Millman closed out the calendar year ranked 128th overall.
Novak Djokovic says he is "really pleased" with his form as he aims to reach the US Open semi-finals for a 12th consecutive time on Wednesday.
Federer had cruised through the first set against Millman who was appearing in his maiden last-16 at the majors.
The win serves as the first time Millman has defeated a top ten opponent, and not only helps him net the biggest pay day of his career, but will nearly certainly propel him to a career-high ranking once the tournament is over.
With the defeat, the 20-time Grand Slam champion failed to set up a highly-anticipated quarterfinal match-up with his Serbian rival Novak Djokovic, seeded sixth.
Go get 'em, Johnno. You lose energy as it goes by.
It doesn't require a particularly extensive search to find the latest tennis obituaries for the late, great Roger Federer after he was put to the sword by unfancied Australian John Millman.
"I love his intensity", said Federer.More news: BBC presenter Rachael Bland dead at 40
"On court, he recognised that he may have got the great one on a rare night off, or an occasion where an ailment had blunted his brilliance", Fairfax media said in an analysis.
It was Federer's first defeat in 41 matches at the US Open against a player ranked outside the top 50.
Federer, perhaps looking and sounding his age, said: 'I just thought it was very hot tonight.
"I felt like a deer in the headlights at the beginning, to be honest with you".
Federer, the five-time champion and looking to end his 10-year wait to add to his total in NY, was beaten by Australia's world number 55 John Millman 3-6, 7-5, 7-6 (9/7), 7-6 (7/3). "I had some pretty bad experiences there", Millman said.
'He reminds me of David Ferrer and those other guys that, you know, I admire a lot when I see them, when I see how they train, the passion they have for the game.
"I'm probably in a little bit of disbelief", he said in a courtside interview. As the unforced errors mounted - Federer would finish with 77, almost three times as many as Millman's 28 - Federer's wife, Mirka, couldn't bear to look, placing her forehead on her hands in the guest box in the stands. I've played in the daytime at 120 (F).
Federer hung his head at a changeover, a little black fan pointed right at his face, but nothing seemed to make him feel like himself. You try to play. "I've got a 7 am fantasy draft, so I'm going to get up for that".
Through his opening-round matches, Djokovic and his play both suffered under a blazing sun and with temperatures nudging 32 degrees Celsius, the extreme conditions took a toll on 31-year-old Serb.