Osaka, quadruple Grand Slam champion, winner at Rinse the meadows in 2018 and 2020, was beaten 7-6 (7/5), 6-3 by 19th-seeded American Collins in a battle of two heavy hitters.
Collins, runner-up at this year’s Australian Open, now moves on to a second-round clash with Spain’s Cristina Bucsa.
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The 28-year-old right-hander from Florida will head into this mission full of confidence after showing great composure to tidy up Osaka at Arthur Ashe Stadium.
Former world number one Osaka, whose ranking fell to 44 after an inconsistent year, started softly with an early break to take a 3-0 lead.
But Collins fought back in the match and won the first set after winning a hard-fought tie-break.
With both players producing booming groundstrokes, the second set was a matter of who blinked first.
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Collins put herself on the verge of victory after beating Osaka to a 5-3 lead in Game 8.
Osaka, 24, came close to getting the break of serve needed to keep the game alive after taking a 15-40 lead in game nine.
But Collins rallied at two and then claimed victory on her first match point when Osaka hit a long return.