Bernarda Pera stunned former French Open champion Barbora Krejcikova at Tennis in the Land as the top three seeds tumbled out in Cleveland.
Pera has enjoyed an excellent 2022, winning her first career WTA title in Budapest and then following that up with her second at the Hamburg European Open.
And the Croatian-born American is two wins away from a third final after thrashing top seed Krejcikova 6-4 6-1.
It sets up an enticing last-eight clash with another former grand slam champion in compatriot Sofia Kenin.
Second seed Martina Trevisan from her clash with Zhang Shuai, while third seed Ekaterina Alexandrova lost 3-6 7-5 7-5 to Maidson Brengle.
Some high seeds also tumbled out at the Granby Championships.
Third seed Jasmine Paolini surrendered a lead in a three-set loss to Rebecca Marino and there were also defeats for fourth seed Anna Bondar and eighth seed Tereza Martincova to Tatjana Maria and Diane Parry respectively.
Marta Kostyuk, the 10th seed, had to come from a set down to beat Marina Stakusic but ninth seed Daria Saville lost just one game in her demolition of Katherine Sebov, winning 6-1 6-0.