The big-serving American prevailed in a deciding tie-break to triumph 6-4 3-6 7-6 (7/3) and will play second seed Tomas Berdych in the final.
Isner has been in fine form since losing in the first round at Wimbledon to Alejandro Falla and believes his run in Winston Salem is the perfect preparation for next week's US Open.
The world number 10 said on atpworldtour.com: "I'm very, very happy to be back in the final. I don't like getting to grand slams early. If I'm playing the week before, I want to do as well as I can.
"I'm playing the final match, so I'm very satisfied with that. I'm looking to defend my title. I did it this year in Newport, so maybe I can pull it off again?"
In the other semi-final, Czech Berdych dashed home hopes of an all-American final with a 6-4 6-3 victory over Sam Querrey.
The result ended Querrey's hopes of overhauling Novak Djokovic and winning the US Open Series, meaning the world number two will earn a bonus of one million US dollars if he successfully defends his US Open title.