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Isner, runner-up in Atlanta in July against American number one Mardy Fish, will play for his third career trophy on Saturday against the winner of a later semi-final between French qualifier Julien Benneteau and Dutch 10th seed Robin Haase.
Inser, who grew up just 50 kilometers from the site of the new ATP event, came to the court standing 1-3 against longtime American number one Roddick.
But a year of injury and poor form took a toll on Roddick, who turns 29 next Thursday during the US Open, with the top seed failing to hold onto a 3-1 lead in the second set as Isner overhauled him to streak to the victory in just over 90 minutes.
Roddick, who had not dropped a service game in 26 coming into the Isner match, was finally broken to start the second set after losing the first in a tie-breaker, with Isner saving a set point on a running forehand down the line.
Though Roddick got out to a lead in the second, Isner was able to haul him in, finishing with 34 winners and half as many unforced errors. His ace count was a modest eight on the day compared to 10 for 2003 US Open winner Roddick.
Isner admitted that a change in the weather helped his cause.
"The sun was the difference - really," said the world number 28. "It went behind the clouds in the second set, I felt a cool breeze and got some energy back.
"I had been struggling a bit after the long first set (which he won in a tiebreaker). I wanted to keep the points short - you can't win a 10 of 15-shot rally with Andy, he's just too good. I started to play offensively."
Isner, who won a trophy on Newport grass the week after Wimbledon, said he was aided by his ability to conserve energy.
"I'm somehow able to spend it at the right time," he said. "It just comes naturally."
Roddick was playing his fourth semi-final of the season but is out of the Top-20, on 21st, for the first time in a decade. His lone title came at Memphis in February.
Isner improved to 16-4 in his past six events as he played a fourth semi-final from six tournaments.
Benneteau, ranked 113th, leads number 42 Haase 1-0 after beating the Dutchman four years ago.
