Isner fired 16 aces and needed only 56 minutes Tuesday to dispatch fellow American Tommy Paul 6-3, 6-3.
Isner fired 16 aces and needed only 56 minutes Tuesday to dispatch fellow American Tommy Paul 6-3, 6-3 and reach the third round at the ATP and WTA Cincinnati Open.
"I played a good match and I'm happy to get off the court in under an hour," Isner said. "When I had break point, I got after it, put good returns on the court and played aggressively."
World number 19 Isner, who won titles last month at Newport and Atlanta, could next face Zverev, who has taken titles the past two weeks at Montreal and Washington, although the 20-year-old German must get past US teen Frances Tiafoe on Wednesday.
"If I do play him, it will be a huge challenge. For me, he's definitely the guy to beat right now on tour," Isner said. "If I do play him, I'll be very much looking forward to that and definitely think I can give him a good tussle."
Spanish top seed Rafael Nadal, the 15-time Grand Slam champion who returns to world number one next week after a three-year absence, faces France's Richard Gasquet in his opener Wednesday after a bye.
World number 10 Milos Raonic of Canada withdrew Tuesday with a left wrist injury, leaving only three of the top 10 in the men's field.
Also among the missing are Roger Federer (back), British world number one Andy Murray (hip), Novak Djokovic (elbow), Stan Wawrinka (knee), Kei Nishikori (right wrist) and Marin Cilic (adductor).
That offers an enticing chance for those who have never won so large a title, even with Zverev and Nadal still in.
"It's an opportunity for a lot of players," Isner said. "I think (Zverev) recognizes that as well. I think he has looked at the draw and seen that Roger is out and Milos is out.
"So I think his eyes are kind of popped wide open again. He's looking for another one."
On the women's side, Wimbledon winner Garbine Muguruza, and second-ranked Simona Halep cruised into the third round.
Romania's Halep, hoping to overtake Czech Karolina Pliskova for the world number one ranking this week, downed US qualifier Taylor Townsend 6-4, 6-1, while Spain's sixth-ranked Muguruza ousted Brazil's Beatriz Haddad Maia 6-2, 6-0.
"I'm happy to be into the third round," Muguruza said.
After trading four service breaks in the first six games, Halep took 11 of the last 12 to dispatch Townsend in 66 minutes.
US ninth seed Venus Williams downed compatriot Alison Riske 6-2, 6-0 to book a second-round match with Australian qualifier Ashleigh Barty.
French Open champion Jelena Ostapenko of Latvia was ousted by Serbian qualifier Aleksandra Krunic 6-4, 6-2 while Russian lucky loser Natalia Vikhlyantseva beat Croatia's Donna Vekic 6-3, 2-6, 6-3 to book a matchup with Czech women's world number one Karolina Pliskova.
Argentina's Juan Martin del Potro, the 2009 US Open champion, hit 17 aces in defeating Czech 10th seed Tomas Berdych 3-6, 7-6 (7/1), 6-0 while Japan's Yuichi Sugita took advantage of 43 unforced errors by Jack Sock to oust the US 13th seed 7-5, 6-4.
Those results left Bulgaria's 11th-ranked Grigor Dimitrov as the only seed in his quarter of the draw.