The Australian men's No.2, who's had a poor run in the senior event in Paris ever since winning the boys' title back in 2017, was in charge of his first match against Yoshihito Nishioka, leading 7-5 6-4 1-2, when the Japanese left-hander had to retire with injury on Monday.
After Sunday's first-day wipe-out with all three Australians exiting - Tristan Schoolkate, Destanee Aiava and Rinky Hijikata - Popyrin reckoned it was a "nice feeling" to break the duck for the 16-strong Australian contingent on a busy second day for the green-and-gold brigade.
And the 25th seed did just that, his path eased immensely once world No.77 Nishioka began to struggle with a lower back complaint near the end of an even opening set and then tweaked the injury again four points before he retired.
Nishioka, who had thrown in a distracted service game to get broken at 5-5 in the first set with three straight unforced errors, had needed a medical timeout for courtside treatment to his back and hip after the opening stanza.
The win was a huge relief for world No.25 Popyrin, who's endured a difficult season with injuries, illness and a break with his co-coach Xavier Malisse as his stellar 2024 form dipped.
"I feel like my game is starting to come back to me, the results are starting to show a bit more, there's more consistency and match wins every week. That's really important," said Popyrin, who tackles another left-hander in his next encounter, Chilean Alejandro Tabilo, a five-set victor over home wildcard Arthur Cazaux.
In the women's singles, Gold Coast's Kim Birrell found the in-form Romanian Jaqueline Cristian too much of a hurdle, battling for all her worth to put just one game on the board at the end of the first set during a 6-1 6-0 hammering.
Cristian had been beaten in the Morocco Open final on Saturday by teenager Maya Joint, who was facing Ajla Tomljanovic later on Monday in an all-Australian battle of the generations.
Earlier, it had been revealed Nick Kyrgios had withdrawn from his planned return in the men's doubles, ending the prospect of his first competitive Roland Garros outing for eight years.
Australia's former Wimbledon finalist Kyrgios, whose recent career has become a stop-start affair riddled with injury concerns, had declared a couple of weeks ago that he planned to play alongside old friend Jordan Thompson in the doubles.
But when the draw was announced on Monday, it was confirmed Thompson was lining up instead alongside fellow Aussie Jason Kubler for a first-round match against French pair Quentin Halys and Albano Olivetti.
Kyrgios will be at Roland Garros, where he last competed in 2017 while reaching the second round, but only off-court as a TV commentator, as he increasingly turns his attention to media opportunities.