Nadal, fresh off a win last week in the hardcourt Rogers Cup at Montreal, continued his roll through the Cincinnati Masters event in the final, besting Isner 7-6 (10-8), 7-6 (7-3).
The 27-year-old Spanish star claimed back-to-back hardcourt wins for the first time in his career, improving to 15-0 on the surface this year while improve to 4-0 all-time against Isner.
The triumph was the 26th in ATP Masters 1000 events for the 12-time Grand Slam champion and his 59th overall career championship, assuring him his first world No. 2 ranking since July 2, 2012.
He fell to 7-9 in title matches.