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.
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.
Into the quarterfinals!@ashbar96 comes back from a set down to defeat Kontaveit 4-6, 7-5, 7-5.#CincyTennis pic.twitter.com/kFuyD6lPJu
— WTA (@WTA) August 15, 2019
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.
.@Naomi_Osaka_ advances to the @CincyTennis quarterfinals!
— WTA (@WTA) August 15, 2019
The No.2 seed battles past Hsieh Su-wei 7-6(3), 5-7, 6-2. pic.twitter.com/Ag37lJfOHc
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.
Keys will face Venus Williams after the American veteran beat Donna Vekic 2-6 6-3 6-3.
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.
.@Madison_Keys books her spot in the @CincyTennis quarterfinals!
— WTA (@WTA) August 16, 2019
The No.16 seed defeats No.4 seed Simona Halep 6-1, 3-6, 7-5. pic.twitter.com/4JvXSXg2SD
Having lost finals in Cincinnati in 2015, 2017 and 2018, Halep fell short of reaching another decider.
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.