Isner, who defeated Belgian Olivier Rochus in last year's Newport finale, this time handled Hewitt by a 7-6 (7-1), 6-4 margin in the decisive match.
The 6-foot-9 American fired off 16 aces to become the first repeat champion at the Hall of Event since France's Fabrice Santoro in 2008.
Australia's Hewitt, a former world No. 1, came up short in his bid for a 29th career title.
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