Barty breezes into last 16 but Kenin, Bencic and Mertens out as seeds scatter in Charleston
Barty – who last featured in a clay-court match en route to Roland Garros glory almost two years ago amid the coronavirus pandemic – made light work of Misaki Doi 6-2 6-1.
Miami Open champion last week, top seed Barty continued where she left off at the WTA 500 event on Wednesday, closing out proceedings in just over an hour in Charleston.
"I had to use it as an opportunity to try and build some comfort," Barty said. "I think having a couple days between Miami and playing this first match was important, to have my body rest, but to also try and prepare to change surfaces. It was a very quick turnaround, but I felt great out there tonight."
Barty – who now boasts a 15-2 win-loss record in 2021 – will next face Shelby Rogers after she outlasted 13th seed Amanda Anisimova 1-6 7-5 6-4.
As for second seed Sofia Kenin, the 2020 Australian Open champion slumped to a shock 4-6 6-3 6-4 defeat against Lauren Davis midweek.
World number four Kenin – runner-up at last year's French Open – eased to the first set but fellow American Davis, ranked 79th in the world, changed tactics to fine effect.
"I was a bit uncomfortable so I just really dug deep and really started to think about how to beat her and I found that heavy deep balls were not her favourite," the 27-year-old Davis said.
"Being on clay, the ball bounces high, pushing girls back, so it's very effective."
Kenin took a medical timeout at 3-0 down in the deciding set but, despite reeling off the next three games, she was unable to see Davis off as her 2021 woes continue.
Davis now heads into another all-American clash with teenage sensation Coco Gauff – who came from 1-3 down in the third to defeat Liudmila Samsonova 4-6 6-1 6-4 in an absorbing two-hour contest.
Belinda Bencic – the fifth seed – crashed out as Paula Badosa claimed the first top-20 win of her career following a 6-2 6-7 (2-7) 6-1 success.
Badosa will face Caty McNally in the last 16 after the 19-year-old American beat Anastasija Sevastova 7-6 (7-3) 2-6 6-4.
Seventh seed Elise Mertens was another big name to depart as Alize Cornet prevailed 7-5 6-3, although 15th seed Veronika Kudermetova and 12th seed Ons Jabeur progressed in with the minimum of fuss.
Former US Open champion Sloane Stephens, meanwhile, topped eighth seed Madison Keys 6-4 6-4.
Seeds were even more vulnerable at the Copa Colsanitas in Bogata, including the top-seeded Saisai Zheng who was dispatched 6-4 6-1 by Stefanie Voegele.
Zheng's compatriot Yafan Wang, seeded eighth, went down 6-3 6-3 to Viktoriya Tomova.
Arantxa Rus and Jasmine Paolini, the third and sixth seeds respectively, lost in three to Spanish duo Nuria Parrizas Diaz and Lara Arruabarrena.