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In the final, Hewitt will face Nicolas Mahut of France, who advanced by beating American Michael Russell 6-2, 6-2.
The loss ended 13 straight match wins in Newport for the 28-year old Isner, the highest ranked American at No 19.
"It's never disappointing losing to a guy like Lleyton Hewitt, especially on this surface," said Isner, who called for the trainer after the first changeover. "I was probably eventually going to lose this tournament. It just happened a little earlier than I thought or wanted."
The 6-foot-10 Isner said he felt pain in his left knee area, similar to what forced him to retire in his second-round match at Wimbledon last month.
"It was obviously not as severe because I was able to continue," he said. "It was a little bit scary. The more I think about it and the more I talk about it, I think it's an issue with my quad because the pain is directly above my kneecap."
But he said it wasn't the reason he lost the match, which was played in bright sunshine under humid conditions, with temperatures in the mid-80s.
"He handled the conditions much better than me, simple as that," he said. "He deserved to win."
Trailing 5-2 in the final set, the second-seeded Isner broke Hewitt's serve in the next game before deflecting three match points in the ninth and closing it with an ace to cut the deficit to 5-4.
At 40-30 the final game, Hewitt ended the match with a forehand cross-court shot. He raised both hands in the air before waving to his wife, Bec, seated in the first row on the far end of the court.
Mahut, a wildcard entrant, needed just 63 minutes to beat Russell, one day after their match was suspended by rain after the third point. Isner and Hewitt never got started on Saturday.
Isner's loss spoiled a rematch with Mahut. The pair played the longest match in tennis history when Isner beat Mahut 70-68 in the fifth set at Wimbledon in 2010 - a match that lasted 11 hours, 5 minutes.
Hewitt won a rematch of last year's Hall of Fame final, won by Isner in straight sets.
Mahut's win began a long day, which includes a semi-final in doubles.
