Williams, a seven-time singles and 14-time doubles Grand Slam champion, was beaten by Czech 11th seed Karolina Muchova in the first round of the women’s singles on Tuesday.
But she impressed during the defeat and later accepted a wildcard invitation to partner 22-year-old Fernandez in the doubles.
The pair’s victory against highly experienced doubles duo Hozumi and Eikeri, of Japan and Norway respectively, means they are yet to drop a set at Flushing Meadows together.
Williams, who had been away from the WTA Tour for 16 months before her return to action in Washington in July, became the oldest singles player in 44 years to play at Flushing Meadows this week.
They will face either British pair Katie Boulter and Sonay Kartal or Ekaterina Alexandrova and Zhang Shuai in the next round.
Elsewhere, Briton Henry Patten and Finnish partner Harri Heliovaara were knocked out in the first round of the men’s doubles by Constantin Frantzen and Robin Haase.
The German-Dutch duo lost the first set on a tie-break but took the following two sets to seal a 6-7 (5-7) 7-6 (11-9) 7-5 victory.
Third seeds Patten and Heliovaara won the Australian Open title earlier this year after being crowned Wimbledon champions in 2024.
Jamie Murray and his Croatian partner Ivan Dodig also exited in a 6-4 6-3 defeat by Brazilian duo Rafael Matos and Marcelo Melo.