Isner, seeded third and ranked 10th, will face seventh-ranked Tomas Berdych of the Czech Republic, a 6-4, 6-3 winner over seventh-seeded Sam Querrey in the final hard-court tournament before the U.S. Open.
Isner, from nearby Greensboro, had 24 aces against the top-seeded Tsonga to reach his fourth final of the season. The American won the grass-court event last month in Newport. R.I.
"I'm playing in the final match, and I'm very, very happy to be able to do that," said Isner, 9-0 in Winston-Salem matches. "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."
Isner also improved to 3-1 against Tsonga, including two wins this year.
While Isner broke Tsonga's serve once in winning the first set, the American lost out on nine other break-point opportunities, including a 40-15 game in the second set and a 40-love game in the third.
"I converted my first one, and missed nine in a row," Isner said. "But he hit two or three outright winners, and that made it a little bit more stressful on myself."
However, Isner bounced back with three mini-breaks in the third-set tiebreaker, closing out the match with an overhead winner.
"I thought I had the momentum when I broke him (in the second set)," Tsonga said. "But when you play a player like John, you know that if he can break you, it's going to get hard (to win)."
The Winston-Salem final berth continued Isner's strong run leading up to the U.S. Open, where he is the ninth seed. Beginning with his win at Newport, Isner has advanced to the quarterfinals or better in his last four events.
"I didn't play that well in the clay court season," Isner said. "I had to turn it around and get back to work, and playing in the U.S. has always seemed to do me well. Winning at Newport took some of the pressure off me, and allowed me to relax the rest of the summer."
In the second semifinal, Berdych overcame 18 aces by Querrey by breaking his serve five times, including the final two games in both the first and second sets to advance to his third final of the season.
"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."
Querrey, who won at Los Angeles last month, did break Berdych's serve three times -- the first game of the first set, and twice in the second set to even things at 3-3 -- but also committed five double faults.
"I played a decent return game, because I broke him several times," Querrey said. "But on my service games, I was giving him too many easy breaks on my own game points. That made it tough."