Nadal, seeded fourth in the Cincinnati Masters event, improved to 14-0 on hard courts this year with a 7-5, 7-6 (7-4) triumph over sixth-seeded Tomas Berdych at the Lindner Family Tennis Center.
The Spanish star was coming off a hard-fought decision over defending Cincy champ Roger Federer in a Friday quarterfinal pairing.
He'll next face Isner, who advanced with a 6-7 (5-7), 7-6 (11-9), 6-3 decision over seventh-seeded former U.S. Open champ Juan Martin del Potro.
The American won for the 16th time in 19 matches since Wimbledon and will be looking for his eighth career title, while Nadal, who is 4-0 all-time against Isner, is seeking his second Masters win in two weeks following his victory last week in Montreal.
2014: The Year in Music [PHOTOS]