Osaka advanced to her first fourth-round match at any major since the 2021 Australian Open by eliminating Australia's No.15 seed Daria Kasatkina 6-0 4-6 6-3 on Saturday.
Earlier, Gauff made it that far for a fourth consecutive year with a 6-3 6-1 victory over Poland's No.28 Magdalena Frech while in the night match world No. 2Iga Swiatek weathered a fierce challenge from Anna Kalinskaya before prevailing 7-6 (7-2) 6-4.
In 2019 Gauff was a 15-year-old making her main-draw debut at Flushing Meadows and Japan's Osaka was the reigning champion.
Osaka won that one in straight sets, then consoled a teary Gauff on the sideline and encouraged her to speak to an Arthur Ashe Stadium crowd that was pulling for the young American.
"I kind of see her as a little sister so it's kind of cool to be playing her here again," said former world No.1 Osaka.
"My recollections were that I remember just knowing that she was going to be a really great tennis player, which I was right.
"Now to be playing her again after six years, I don't know if that makes me old, but just to be at this point of my life and to be playing her again honestly, for me, feels kind of special."
Since then No. 3-seeded Gauff, 21, is now a two-time grand slam champion, including at the US Open in 2023.
Now ranked world No.24, Osaka, 27, owns four major titles - including at the US Open in 2018 and 2020 - has become a mother and a mental health advocate.
Meeting for the first time at the US Open since that unforgettable 2019 night, Gauff has dominated their head to head battles, winning three of their four.
"I remember it was a tough moment for me, because it was a hyped-up match and I guess I put way too much pressure on myself," Gauff said.
"It would be a cool, kind of, deja vu type of situation but hopefully it will be a different result."
Poland's Swiatek looked anything but comfortable as Kalinskaya raced to a 5-1 lead in the opening set.
The 29th seeded Russian appeared poised to repeat her stunning victory over Swiatek in Dubai last year, but the 2022 US Open champion clawed her way to a tiebreak where she dominated 7-2.
Kalinskaya continued to trouble the six-time Grand Slam champion with aggressive baseline play.
But the Pole found her range when it mattered most, securing the decisive break in the second set at 5-4 and closing out the match.
"Anna was playing great. She was really playing all these risky balls it like she once did against me in Dubai," said Swiatek.Â
"I wanted to make less mistakes, I was playing good but in the last shots I couldn't finish it."
Swiatek will next face Russia's 13th seed Ekaterina Alexandrova, who swept past German Laura 6-0 6-1.
Other women into the fourth round included Czech 11th seed Karolina Muchova, a US Open semi-finalist in 2023 and 2024, and Ukrainian world No.28 Marta Kostyuk while American Amanda Anismova battled to a three-set win over Romanian Jaqueline Cristian.
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