The French Open and U.S. Open champion has won five titles this season and is closing in on the year-end No. 1 ranking.
"I don't remember a lot of mistakes," Nadal said. "I went to the net very often. I did the things that I want to do, and I did it well, so very happy."
On the women's side, unseeded Carolina Garcia of France upset third-seeded Elina Svitolina of Ukraine 6-7 (5), 7-5, 7-6 (6) in almost 3 1/2 hours to line up Petra Kvitova in the semifinals. Simona Halep, on course to becoming the No. 1 player in the world for the first time, faces French Open champion Jelena Ostapenko.
Nadal saved all three break points he faced against Isner. He will next play third-seeded Grigor Dimitrov, who defeated Roberto Bautista Agut 7-6 (5), 4-6, 6-2.
Dimitrov spent time practicing with Nadal in Mallorca ahead of the hard-court season. The two also went fishing at sea.
"We catch a few ones (fish), but not very big," Nadal said. "But we had some good dinner."
Nick Kyrgios also advanced. The eighth-seeded Australian won when opponent Steve Darcis retired with a neck strain while trailing 6-0, 3-0.
Kyrgios will take on second-seeded Alexander Zverev. The German beat Andrey Rublev 6-2, 6-3 and qualified for the season-ending tournament in London.
"It's great for any player to qualify," said Zverev, who has five titles this season.
Second-ranked Halep moved into the women's semifinal by defeating Daria Kasatkina of Russia 6-2, 6-1.
To bump Garbine Muguruza from No. 1, the Romanian needs to reach the final. Halep's quarterfinal win avenged her straight-sets loss to the 34th-ranked Kasatkina at Wuhan last week.
Kvitova defeated Czech countrywoman Barbora Strycova 6-3, 6-4. Kvitova has won the last 24 matches she's played against fellow Czechs.
"We are pretty good friends from the Fed Cups," she said. "We know each other well. We practice a lot as well. Maybe it's extra motivation for us to play each other."
Ostapenko beat Sorana Cirstea 6-4, 6-4 in an error-filled quarterfinal.