"I think I played a solid match," the Spaniard said afterward. "I played very well, changing good directions.
"I think on return I did well. It's an important victory for me, of course, against a player that arrived here playing so well, winning two great matches. For me it's an important one and I'm very happy."
Nadal broke Isner's serve at 5-4 in the first set and then recovered from 15/40 in the second game of the second set before sweeping through the tie-break. Nadal is now an ATP World Tour-best 59-9 (32-7 on hard courts) in 2017 and continues his quest for a 75th tour-level crown.
Nadal leads Dimitrov 8-1 in their head-to-head matches.
"He is a player that I really like, a good friend on the Tour," Nadal said of Dimitrov. "He's a great guy. I think Grigor is a player always with a great attitude, with a positive character. I'm happy for him that he's having a good year. Tomorrow will be a tough one, for sure. He's playing well. He had a good victory today. Let's see. I going to try to play my best. I hope to be ready for it."
Kyrgios will next face Alexander Zverev of Germany after the No. 2 seed stopped Andrey Rublev of Russia 6-2, 6-3.