The reigning champion did not even have to be at his very best on Thursday as he dismantled the dangerous Australian 6-3 6-2 6-2 in their one-sided US Open duel on Arthur Ashe Stadium.
Popyrin, who had knocked out Novak Djokovic at Flushing Meadows in 2024, was exactly the sort of opponent Sinner would have wanted to avoid in the last-64 but, in truth, the battling Sydneysider never really laid a glove on him as he sought to take out a defending champ for the second year running.
Sinner's serve may not have been functioning as he would have hoped but the rest of his game was in formidably good order as he wrapped up his 23rd consecutive grand slam hard-court triumph and looked as if he's in the sort of suffocating, relentless mood to make it four triumphs in the last five grand slams.
Popyrin, Australia's No.2 player and world No.36, had his moments in the second and third sets, often trying his luck with some success at the net, but Sinner repelled all five of the break points he faced in two separate games. Not only that, but he then went on to break to love in the very next games.
The illness that derailed Sinner in the Cincinnati Open final against Carlos Alcaraz last week already felt like ancient history as Sinner's fast start helped him breeze through the first set with his only concern seemingly being to get a foot blister treated at the end of the stanza.
Popyrin had won the pair's only previous meeting on clay in Madrid four years ago but that too felt like a bygone age as the Australian was soon on the back foot again, despite showing admirable resistance to win the longest rally of the match which, momentarily at least, left the Italian a mite breathless.
But the way Sinner hit back was ominous indeed for the rest of his opponents, as he took the racquet out of Popyrin's hands with his blistering 26 winners while applying familiar relentless pressure.
Even though he was getting his first serve in only 55 per cent of the time, he ended up sending a sixth ace down the T to seal his win in just a minute over two hours, setting up a third-round contest with Canadian No.27 seed Denis Shapovalov, who beat Frenchman Valentin Royer 7-6 (8-6) 3-6 7-6 (7-4) 6-3.
Playing through back pain, German third seed Alexander Zverev defeated Britain's Jacob Fearnley 6-4 6-4 6-4 and will face Canadian Felix Auger-Aliassime for a spot in the round of 16.
Australian eighth seed Alex de Minaur and American 14th seed Tommy Paul also progressed.
But two-time grand slam runner-up Stefanos Tsitsipas lost in five sets to German Daniel Altmaier, who will meet de Minaur next.
