World number seven Zverev, who stunned Roger Federer in the Montreal final last week after claiming the title in Washington DC, was on a 10-match winning streak but faded in the final set against the energetic baseliner.
It was 19-year-old Tiafoe’s first win over a top-10 player and he bounded around the court in joy, thumping his chest to a standing ovation after Zverev floated a backhand long on match point with his third unforced error of the last game.
“I saw he was a bit tired, but he was still competing. It was tough. I was happy to get through it,” 87th-ranked Tiafoe told Tennis Channel. “My game plan was to keep the rallies long and keep him out there and that’s what I did.”
Tiafoe, who notched his first top 50 win in Wimbledon, will meet big-serving American John Isner next up.
“I just got to weather the storm,” Tiafoe said. “He’s going to drop some big-boy heat on me and I’m going to have to be ready for it.”
Earlier, Bulgarian seventh seed Grigor Dimitrov beat Feliciano Lopez 7-6(5) 6-4 to set up a last-16 clash with Juan Martin Del Potro.
Dimitrov nearly broke the unseeded Spaniard three times prior to making a strong start in the tiebreak and went on to register 27 winners in the match.
The 28-year-old Del Potro, playing at Cincinnati for the first time in four years after reaching the semi-finals in 2012 and 2013, advanced with a 6-4 6-4 win over American qualifier Mitchell Krueger, winning each set on a late break.
Del Potro, who on Tuesday ousted 10th-seeded Czech Tomas Berdych, saved five break points at 3-3 in the second set and clinched victory on his fourth match point.
Dimitrov has not beaten Del Potro in five career meetings, with the most recent defeat coming at Rome in May.
Australian Nick Kyrgios beat Ukraine’s Alexandr Dolgopolov 6-3 7-6(6) to reach the third round, where he will face unseeded Croatian Ivo Karlovic.
Also advancing to the round of 16 were Spaniards David Ferrer and Pablo Carreno Busta, and Russian Karen Khachanov.
Top-seeded Spaniard Rafa Nadal will cap off the night session when he meets Frenchman Richard Gasquet.
