Two days after pulling off a shock win against world No.6 Felix Auger-Aliassime, Popyrin sent down 16 aces and 40 winners to power past Giron 4-6 6-4 6-3 at Adelaide's Memorial Drive on Wednesday night.
Popyrin battled a series of niggling injuries and a loss of confidence last year on the way to compiling a disappointing 5-17 win-loss record in ATP Tour events.
But the Sydneysider's start to 2023 has been ultra impressive, and he now has a chance to make further inroads when he takes on world No.36 Yoshihito Nishioka in the quarter-finals.
The defining moment of the match came with scores locked at 3-3 in the third set.
Popyrin hit the ground after diving for a volley, and while on his backside played another net shot to win the point.
With the crowd on their feet, Popyrin used the momentum to hold serve and then get the break, with the world No.120 full of energy after sealing the win in one hour 52 minutes.
"In the first set my level wasn't great, but he played well and didn't miss any balls," Popyrin said.
"It made it difficult for me. But I stuck with it, I served pretty well throughout. That kept me in the match.
"And then when I had my opportunities to break, I tried to capitalise on it."
At one point during the match, Popyrin hid his head under a towel while giving himself a pep talk.
"I was just trying to mentally get myself back into the match," he said.
"There was probably some swear words I was telling myself under the towel."
Earlier, Daniil Medvedev eased into the final eight by beating Miomir Kedmanovic 6-0 6-3.
Currently ranked seventh in the world and seeking a return to the top spot he owned less than a year ago, the Russian broke four times and combined 32 winners with 13 unforced errors.
He will play his good mate Karen Khachanov for a spot in the semi-finals.
"It was a great match; Miomir is a tough opponent, high-rep player," he said after his 67-minute procession.
"There are no easy guys left in Adelaide, not sure there were even in the first round.
"Really happy to be through, happy with my level and looking forward to my next match."
Khachanov, the former world No.8 and a semi-finalist at last year's US Open, beat Briton Jack Draper 6-4 6-2 in 91 minutes at Memorial Drive.
Nishioka beat Mackenzie McDonald 6-4 6-3 to set up his date with Popyrin.
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