In the Australian's first match since losing to Jannik Sinner in the round of 64 at the US Open, Popyrin has fallen at the first hurdle to Sebastian Korda, going down 6-7 (4-7) 6-1 6-3 at the indoor hardcourt event on Monday night.
The seventh-seeded Australian had split the two previous clashes with the American but the world No.48, who had enjoyed reaching a career-high 19 just prior to playing at Flushing Meadows, succumbed in two hours 24 minutes.
Both men lost their serve twice in the opening set, while Popyrin was broken a further five times en route to Korda setting up a second-round clash with a fellow unseeded opponent.
Other first-round winners included Swedish wildcard Leo Borg, son of 11-time grand slam winner Bjorn, Brit Jacob Fearnley and Serbia's Miomir Kecmanovic.
Meantime at the ATP 250 hardcourt event in Almaty, James Duckworth was a 6-3 6-4 opening-round winner over fellow qualifier Ugo Blanchet, one day after the Frenchman eliminated another Aussie in Rinky Hijikata.
But compatriot Bernard Tomic was beaten in Kazakhstan, 6-1 7-6 (11-9) by eighth seed Corentin Moutet in just under two hours.
Duckworth faces seventh seed Gabriel Diallo next after the Canadian saw off local Amir Omarkhanov, 6-3 6-1.
Defending champion and top seed Karen Khachanov received a first-up bye.
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