The 16-year-old American was broken seven times and appeared frustrated at her service game as she hit 10 double faults, but she stayed the course to beat the Belarusian who had 14 double faults.
The win, which will see Gauff’s enter the Top 50, was just her third career Top 20 victory following triumphs over Kiki Bertens in Linz last year and Naomi Osaka at the Australian Open in January.
3️⃣rd Top 15 win of her career 🙌@CocoGauff defeats the No.2 seed Sabalenka, 7-6(4), 4-6, 6-4.#TSOpen pic.twitter.com/oYXaqX8ToM
— wta (@WTA) August 12, 2020
Earlier, eighth seed Ons Jabeur shook off qualifier Olga Govortsova to book her place in the Lexington quarter-finals, defeating the Belarusian 3-6 6-2 6-4.
Czech world number 48 Marie Bouzkova saw off 21-year-old Russian Ana Blinkova 6-4 6-2 in the other last 16 clash in Kentucky.
Krystina Pliskova dismissed second seed Petra Martic 6-1 7-5 to deliver the biggest shock yet at the Prague Open.
The world number 69 continued her resurgence on clay with her eighth run to a WTA quarter-final on the surface since 2017.
.@KrisPliskova moves 🔛
She takes it over Martic, 6-1, 7-5. #PragueOpen2020 pic.twitter.com/WDFdee3zcc— wta (@WTA) August 12, 2020
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“I feel I’m playing better on clay each year,” said Pliskova.
“Everybody was saying I cannot move and stuff, but I don’t think it’s like this; I have more time, so it’s good for me that clay is not that fast, I can focus on my game.
“We grew up on clay, we practised on clay, we played every tournament on clay, and everybody was saying we would be better on grass or hard courts, but I was still thinking my preference was that it was slow.
It's on to the @TennisPragueOpn quarterfinals for @elise_mertens!
She bests Giorgi 6-4, 6-2 pic.twitter.com/rALSjnj1X2— wta (@WTA) August 12, 2020
“So then I started working a bit on the movement and other things, not just the serve and return, and now I’m getting more confident on clay.”
Elise Mertens ground past Camila Giorgi 6-4 6-2 to reach the last eight, in a dogged victory in one hour and 44 minutes.
Romania’s Ana Bogdan was handed a walkover past Ukraine’s Lesia Tsurenko, who retired before the last 16 encounter.