Hamilton finished 0.6 seconds ahead of pole-sitter Vettel in the inaugural race on the new Circuit of the Americas road course at Austin, Texas.
Hamilton -- who last won the USGP in 2007 at Indianapolis Motor Speedway -- logged his fourth win of the season and the 21st of his F1 career.
Fernando Alonso claimed third place, falling 13 points behind two-time defending champion Vettel heading into next week's season-ending Brazil Grand Prix.
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