Fernandez is now the youngest woman to reach the final four in Flushing Meadows since 18-year-old Maria Sharapova did so in 2005.
Felix Auger-Aliassime reached his first Grand Slam semifinal after Carlos Alcaraz retired following the fourth game of the second set in Arthur Ashe Stadium.
The US Open 2021 saw Angelique Kerber get knocked out in the fourth round while the men's top seeds did not suffer a jolt.
Defending champion Osaka, who suffered a stunning loss in the US Open third round, does not know when she will play again.
18-year-old Spaniard Carlos Alcaraz, ranked 55th in the world, upset No. 3 Stefanos Tsitsipas, 6-3, 4-6, 7-6, 0-6, 7-6 to advance to the fourth round of the 2021 US Open.
Leylah Fernandez dismissed defending champion Naomi Osaka 5-7, 7-6, 6-4, to break through to the Round of 16 of a major for the first time.