One day after Thompson eliminated world No.2 Alexander Zverev to throw the Japan Open wide open, Popyrin proved to be another giantkiller when he sent the seventh-ranked Karen Khachanov packing.
Popyrin defeated the Russian 6-4 6-2 on Tuesday to reach the last 16 of the ATP tournament.
It was a commanding performance from the 24-year-old Sydneysider who dished out 11 aces to Khachanov's seven, and won 90 per cent of his first serves.
He converted four out of 10 break-point opportunities while only losing serve once.
Popyrin will now meet Chilean Christian Garin, who overcame Sho Shimabukuro 6-4 3-6 6-3, for a berth in the quarter-finals.
And joining compatriots Thompson and Popyrin in the round of 16 is Alex de Minaur.
But Australia's top-ranked player didn't have things his own way against a spirited Jack Draper, as the pair battled for three hours and five minutes.
The tournament No.4 seed dropped the first 6-4, but then topped the Briton with two gritty efforts in tiebreakers winning 7-4 and 7-1.
De Minaur now takes on Argentinian Diego Schwartzman, who beat countryman Francisco Cerundolo 6-4 6-1, for a place in the last eight.
Thompson will now meet in-form American left-hander Ben Shelton, who trumped local qualifier Taro Daniel 3-6 6-4 7-6 (7-2), in the next round.
Top-seeded American Taylor Fritz emerged unscathed in his encounter with Cameron Norrie, severing 13 aces on his way to beating him 6-3 6-3.
The 25-year-old American will next play Japanese wildcard Shintaro Mochizuki, who beat Tomas Martin Etcheverry in straight sets.
Casper Ruud, the No.2 seed, defeated another Japanese wildcard, Yosuke Watanuki, 7-6 (10-8) 6-3. Rudd next faces American player Marcus Giron.
Aslan Karatsev put out the American No.6 seed, Frances Tiafoe, 6-3 7-6 (7-4) and will face the winner of the match between Zhang Zhizhen and Hubert Hurkacz.
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