Unbeaten on the surface this year and coming off a win in Montreal, the third ranked Nadal ran his record on the pavement to 15-0 winning back-to-back hardcourt finals on consecutive weeks for the first time in his career.
Nadal needed nearly two hours on a muggy centre court to tame the towering in-form American, who had knocked off three top 10 players, including world number one Novak Djokovic, to earn his spot in the final.
But the big-hitting Isner had no answers for the relentless Nadal, who has now claimed nine titles from 12 events this season.
It was the 59th win of Nadal's career but first in nine tries on the Cincinnati hardcourts.
Image: Rafa Nadal
Photograph: Matthew Stockman/Getty Images