Top seeded German Zverev was well below his best in a 6-3 6-4 defeat by American teenager Learner Tien on Wednesday, while fifth seed Shelton crashed out 7-6 (7-3) 6-3 to David Goffin.
"I just went out there and tried to control my side of the court," said Tien, who is into his second tour-level quarter-final.
"Obviously I knew it was going to be a tough match. To come through feels great ... I think just focusing on what I can control and keeping my cool as best as I can has really taken me a long way."
Last year's runner-up and second seed Ruud pulled out shortly before his match against Rodrigo Pacheco Mendez, sending the local favourite through to the quarter-finals.
"I was hoping to overcome this stomach illness that showed up yesterday," Ruud said on Instagram, adding that he had tried everything he could until the last moment to be able to play.
"Hoping to come back stronger in a couple of days and come back here to Mexico next year."
American third seed Tommy Paul withdrew with a similar problem ahead of his meeting with countryman Marcos Giron, who now takes on Denis Shapovalov after the Canadian beat Alex Michelsen 6-4 6-3.
Michelsen also needed medical attention during that match.
Fourth seed Holger Rune was able to take to the court against Brandon Nakashima but threw in the towel while trailing 3-0 in the opening set.
"Furious and so sad at the same time. Had food poisoning and was unable to play today," Rune said on X.
"One of my favourite places is Mexico and I love this tournament. Absolutely not the way I wanted it to end."
In a late contest, Alejandro Davidovich Fokina sent seventh seed Frances Tiafoe packing, 6-3 6-7 (6-8) 6-3.
