Defending champion Isner, who was born in nearby Greensboro, edged a tight match in a deciding tie-break to record a 6-4 3-6 7-6(3) over the Frenchman.
In Saturday's title match Isner will meet Tomas Berdych, who dashed home hopes of an all-American final by beating Sam Querrey 6-4 6-3 in the other semi-final.
Isner relied on his trademark serve to keep Tsonga at bay, the third seed booming down 24 aces on his way to victory.
"I'm playing in the final match, and I'm very, very happy to be able to do that,'' said Isner.
"I made it a little more stressful on myself with all the break points, but in the end I'm happy to get through it. It could've been easier, but it never is when we play each other.''
In the other semi, Querrey, like his compatriot, used his serve as his main weapon - he fired down 18 of them in total - but it was not enough to see off second seed Berdych, who wrapped up a straight-set victory in just under an hour and 40 minutes.
"I was trying to get my chances,'' Berdych said. "The one thing I was not happy with was my serve in the second set. But I was playing better on the tough and deciding points.''
The tournament in North Carolina serves as a warm-up event for the US Open, which starts in New York on Monday.