Juan Martin del Potro was stunned in the Delray Beach Open quarter-finals, while John Isner moved into the last four on Friday.
Del Potro's first tournament back from a knee injury was ended by Mackenzie McDonald, who upset the Argentine top seed 6-4 3-6 7-6 (7-5).
The 2011 champion was unable to take either of his two break-point chances in the final set, edged by McDonald after two hours, 19 minutes.
McDonald will meet Radu Albot, who surprised fourth seed Steve Johnson 1-6 6-3 7-6 (7-5).
Isner made it seven wins in eight meetings with Adrian Mannarino thanks to a 7-6 (7-2) 6-4 victory.
The American will meet Dan Evans, the British qualifier having upset Italian sixth seed Andreas Seppi 6-4 6-4.
At the Rio Open, Pablo Cuevas remained on track to become the first man to win the ATP 500 event twice.
The Uruguayan 2016 champion overcame a second-set blip to get past Albert Ramos-Vinolas 6-3 3-6 6-3.
Awaiting him in the semi-finals is Felix Auger-Aliassime, the 18-year-old Canadian having claimed a 6-4 6-3 win over Jaume Munar.
The other last-four clash will be between Laslo Djere and Aljaz Bedene, who continued their runs.
Djere, who stunned Dominic Thiem in the first round, beat qualifier Casper Ruud 6-4 7-5.
Bedene eliminated third seed Marco Cecchinato in his opener and moved into the semi-finals courtesy of a 4-6 6-2 6-3 win over Hugo Dellien.