Pole-sitter Vettel, who won his fourth consecutive F1 world championship last month in India, surrendered the lead only once during the 56-lap race at Circuit of the Americas.
It was the Red Bull driver's 12th of the season and the 38th of his career, as well as his first at the U.S. event in three tries.
Should he win the season-ending event in Brazil next week, he would tie Alberto Ascari's mark for most consecutive victories overall, accomplished over two seasons from 1952-53.
Romain Grosjean claimed second place, 6.2 seconds off the pace.
Swim Week Miami Beach 2014 [PHOTOS]