The 27-year-old Spaniard took advantage of the few openings he got Sunday against the top-ranked American, grinding out a 7-6 (8), 7-6 (3) win at the Western & Southern Open that added yet another title to his sensational summer.
He won the title in Montreal a week ago and now has back-to-back hard-court championships for the first time in his illustrious career. He'd never even reached the finals in Cincinnati.
"To win in Montreal and now here in Cincinnati means a lot to me," he said.
It was his fifth Masters title of the season, a career best. Nadal is now tied with Novak Djokovic for most Masters titles in a season since 1990. He's won seven of the nine Masters events during his career.
Given the way he's playing, there could be much more ahead the rest of the year.
Nadal has dominated the tour after overcoming a knee injury that sidelined him for the last part of 2012. The win on Sunday gave him a career-best mark of 53-3 this season. He's reached the finals in 11 of his last 12 tournaments, underscoring his consistent excellence.
He had one of his biggest challenges on Sunday -- the 6-foot-10 Isner, who had the tournament's nastiest serve and the crowd at center court behind him.
Wasn't enough to get Nadal off his game.
He survived a pair of set points in the opener, sending it to a tiebreaker. The crowd chanted "Let's go Isner!" during a changeover during the tiebreaker, which ended with Isner dumping a service return into the net and Nadal pumping his fist.
One set to go.
Isner didn't waver, keeping up with a serve that topped out at 141 mph. Nadal survived the only break point of the second set, taking it to another tiebreaker. The crowd chanted Isner's name again, but it didn't help. He hit a backhand and a forehand into the net, allowing Nadal to go up 5-1 in the tiebreaker.
Nadal finished it with a backhand passing shot from the baseline, then plopped on his back in celebration of his breakthrough. He never got to a break point during the match, but won it by playing so well in the tiebreakers.
"I have to be patient and wait for my opportunities," Nadal said. "And I waited."
Even with the loss, it was quite a week for Isner.
While Nadal spent last week winning the Rogers Cup, Isner was knocked out in the first round and fell to No. 22, the first time in the 40 years of ATP rankings that no American man was in the top 20. He'll be back there next week after reaching the finals in Cincinnati on the strength of his serve.
The 28-year-old American upset No. 1 Djokovic in Cincinnati, a moment he called one of the best of his career. It was the most notable upset of the week. Djokovic hasn't won in Cincinnati -- he's reached the finals four times and lost -- and was especially motivated to finally break through. A title in Cincinnati would make him the first to win all nine Masters events during his career.
Isner beat him in the quarterfinals. On Sunday, he was trying to become the first unseeded player to win in Cincinnati during the Open Era since 1968.
"I thought I played well," Isner said. "Unfortunately for me, I ran up against one of the greatest tennis players of all time."