Former champion Victoria Azarenka was ousted by Barbora Krejcikova while fifth seed Maria Sakkari fell to Jessica Pegula in the Australian Open fourth round.
Azarenka, who won the title in 2012 and 2013, fell to French Open winner Krejcikova 6-2 6-2.
Greece's Sakkari was beaten 7-6 (7-0) 6-3 by former semi-finalist Pegula.
Madison Keys continued her strong form with victory over Spanish eighth seed Paula Badosa.
Keys will face Krejcikova next, while Pegula will face either top seed Ashleigh Barty or American compatriot Amanda Anisimova.
Azarenka's exit means that Rafael Nadal is the only former Australian Open champion remaining in either the men's or the women's draw.
The Belarusian took a medical timeout for treatment to her neck during her match against Krejcikova.
Czech Krejcikova, who has yet to drop a set at Melbourne Park, is in contention for the world number one ranking along with Ashleigh Barty and Aryna Sabalenka.
"It was really amazing today because she is a champion here and I really admire her," Krejcikova said.
"It was a dream to play in a court like this and against such a champion."
Former US Open finalist Keys needed just 71 minutes to beat Badosa and secure her place in the quarter-finals.
Keys won the title in Adelaide in the build-up to the Australian Open and is on a 10-match unbeaten streak.
Compatriot Pegula described her win over Sakkari as her "best match of the year"" as she outlasted the Greek in the Melbourne heat.