This was Osaka's first time reaching the third round of the Championships in seven years, having missed previous tournaments due to mental health issues, injury, and pregnancy.
Sixth seed Madison Keys also exited the women's singles draw after a straight-sets defeat to veteran German Laura Siegemund, 6-3 6-3.
Keys' loss means she is the sixth top-10 player to be knocked out of the women's tournament.
Osaka expressed significant frustration and negativity about her performance following the defeat, stating she had nothing positive to say about herself.