Australia's Daria Saville upset top-seeded defending champion Jessica Pegula 7-5, 6-4 on Wednesday at the ATP and WTA Washington Open, where Hubert Hurkacz and Simona Halep also exited.
World number 88 Saville ripped the seventh-ranked American in hot and humid conditions while Romanian third seed Halep retired down 7-5, 2-0 to Anna Kalinskaya with illness.
"I stayed really composed," Saville said. "I managed the energy really well. It was very hot. But I thought it's hot for everyone so get on with it."
Saville booked a quarter-final match against Canadian qualifier Rebecca Marino, who beat Germany's Andrea Petkovic 6-3, 3-6, 6-1.
Polish second seed Hurkacz crashed out in his second-round match at the US Open hardcourt tuneup, falling to Finland's Emil Ruusuvuori 6-4, 7-6 (7/3).
His third-round foe will be Sweden's Mikael Ymer, who ousted 15th seed Aslan Karatsev 6-4, 3-6, 6-4 after eliminating three-time Grand Slam champion Andy Murray in round one.
Japan's Yoshihito Nishioka ousted Aussie 11th seed Alex De Minaur 3-6, 7-6 (8/6), 6-2. The world number 96 will next face seventh seed Karen Khachanov.
US third seed Taylor Fritz beat Australia's Alexei Popyrin 6-4, 6-3 to book a third-round match against British 16th seed Daniel Evans.