Madison Keys ended Simona Halep's chances of reaching another Western & Southern Open final, while Naomi Osaka and Ashleigh Barty battled through.
A three-time runner-up in Cincinnati, Halep was edged by Keys at the WTA Premier event on Thursday.
The Romanian became the first top-four seed to fall, with Barty, Osaka and Karolina Pliskova booking their spots in the quarter-finals.
KEYS EDGES HALEP IN THRILLER
Keys, the American 16th seed, served 10 aces on her way to a 6-1 3-6 7-5 victory over fourth seed Halep in the third round.
Halep came from 3-0 down in the final set and saved a match point in the 10th game, but Keys broke again to claim her win.
Having lost finals in Cincinnati in 2015, 2017 and 2018, Halep fell short of reaching another decider.
Keys will face Venus Williams after the American veteran beat Donna Vekic 2-6 6-3 6-3.
BARTY, OSAKA MOVE THROUGH
Barty was pushed before getting past Anett Kontaveit 4-6 7-5 7-5 in two hours, 10 minutes.
The Australian found herself 5-3 down in the final set before winning four straight games to advance.
Barty will meet Maria Sakkari, who upset Belarusian ninth seed Aryna Sabalenka 6-7 (4-7) 6-4 6-4.
Osaka was also forced to three sets by Hsieh Su-wei before claiming a 7-6 (7-3) 5-7 6-2 victory.
Awaiting the Japanese star in the last eight is Sofia Kenin, who beat Elina Svitolina for the second time in as many tournaments with a 6-3 7-6 (7-3) victory.
PLISKOVA, KUZNETSOVA PROGRESS
Pliskova, the 2016 champion, is yet to drop a set and was too good for qualifier Rebecca Peterson 7-5 6-4.
The Czech will meet Svetlana Kuznetsova after the 34-year-old wildcard crushed Sloane Stephens 6-1 6-2.