Popyrin's new-found fitness paid huge dividends as he backed up less than 48 hours after a five-set marathon to produce another stirring 6-7 (4-7) 7-6 (7-2) 6-4 6-7 (6-8) 6-2 win on Thursday.
The 23-year-old wildcard hammered 19 aces and dropped serve only once in a thrilling and gruelling four-hour, two-minute test of physical and mental will against the in-form eighth seed.
Popyrin, who slipped to 113 in the rankings following a difficult 2022 season, upset world No.6 Felix Auger-Aliassime on his way to the Adelaide International quarter-finals this month.
He joined in local fans' chants of "Poppy! Poppy!" as tears flowed after his latest shock victory.
"This win means so much to me," Popyrin said.
"I had the toughest year last year. I didn't win many matches.
"I've won as many matches this year as I won last year and it's only January."
Popyrin said his strong pre-season preparation had given him belief and the physical capability to stay the course throughout his opening two matches.
"I put my head down and worked as hard as I possibly could," he said.
"I don't want that feeling that I had last year ever again.
"That I wrote down to myself in my head and I'm going to keep working, keep pushing and I'm going to try and keep going all the way, man.
"I love this feeling and I want more of this feeling."
A hero of Team USA's season-opening United Cup triumph in Sydney, Fritz hurt his right ankle late in the third set and complained about crowd noise during the fourth.
Popyrin, meanwhile, rode the energy of the fans at John Cain Arena and served brilliantly, bashing 74 winners to snare his most impressive win yet at Melbourne Park.
He previously advanced to the last 32 in 2019, when seventh seed Dominic Thiem retired hurt, and again in 2020.
Also a winner at the Indian Wells Masters 1000 last year, Fritz called a medical timeout after Popyrin won the third set to storm to a two-sets-to-one lead.
Popyrin regrouped after failing to convert a match point in the fourth-set tiebreaker to break Fritz for a third time, then a fourth, and claim the most significant win of his career.
Popyrin will take on another American, world No.89 Ben Shelton, in the third round with a golden opportunity to reach the second week of a grand slam for the first time.
