Hours after No. 5 Milos Raonic crashed out of the U.S. Open men's draw, women's No. 3 seed Garbine Muguruza was upset by Anastasija Sevastova in the second round.
Muguruza, who won the French Open in June, was flat on Wednesday night as Sevastova prevailed 7-5, 6-4.
Elsewhere, Madison Keys cruised to the third round, while Lucas Pouille won a five-set marathon over Marco Chiudinelli after trailing two sets to love.
Rafael Nadal will cap the night session against Andreas Seppi at Arthur Ashe Stadium.
For a look at Wednesday's day session, check out SI.