High seeds John Isner and Sam Querrey were sent packing in three sets, while No. 1 seed Jack Sock survived a scare at the ATP Tour's Houston event.
Second-seeded Isner was ousted by fellow American Ernesto Escobedo 7-6 (8/6), 6-7 (6/8), 7-6 (7/5) and third-seeded Querrey lost 6-4, 3-6, 6-3 to Brazilian eight-seeded Thomaz Bellucci in the quarter-finals.
Sock avoided an upset, advancing to the semi-finals with a 7-6 (8/6), 1-6, 6-4 victory over Feliciano Lopez of Spain.
The 20-year-old Escobedo beat former tournament winner Isner despite posting just 10 aces to his opponent's 35.
Fourth seed Steve Johnson eased through to the semis with a 6-2, 6-4 victory over Spanish fifth seed Fernando Verdasco.
Escobedo, who is ranked No. 91 in the world, will face Bellucci in the semi-finals.
Escobedo is competing in his first clay-court tournament and just his ninth ATP Tour event overall.
"I can't believe it," Escobedo said. "To do it here in Houston, it's amazing.
"(It's) such a relief. Past years I've been training so hard and now it's paying off."
Isner was trailing 6-5 in the third set when he fought off three match points and then blasted an ace to force the tiebreak.
He hammered two consecutive aces in the tiebreak to pull within 6-5 but Escobedo clinched the victory with his 10th ace.
"After the second set, I just refocused and told myself to keep on going, be patient and it's gonna happen," Escobedo said.
Sock, who posted his first ATP Tour title here two years ago, is seeking his third title of the year after winning in Auckland, New Zealand and Delray Beach, Florida.
He survived a tough first set in his match and then bounced back after Lopez dominated the second set.