Hamilton, who can secure a fourth world championship on Sunday if results go his way, dominated Friday's sessions and completed the sweep with a fastest lap of one minute 34.478 seconds at a cloudy Circuit of the Americas.
The lap was another track record for the Briton, who had set the previous best of 1:34.668 was set in Friday's second practice.
Vettel, 59 points behind in the championship with four races remaining, was right behind however.
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The German's best effort was 0.092 slower, setting up the prospect of another close battle between the two for pole position.
Hamilton has won four times in the past five years in Austin and another win will hand him the title if Vettel finishes lower than fifth.
Vettel had complained about the 'jelly-like' handling of his car on Friday, when he spun off, with Ferrari changing the chassis overnight.
The car passed scrutineering before the session and there will be no grid penalty.
Red Bull's Max Verstappen, the race winner in Malaysia and second in Japan, will pick up a 15 place drop after elements of his car's power unit were changed, a penalty that will also make life easier for Vettel.
Valtteri Bottas was third in practice for Mercedes, who look sure to clinch the constructors' championship on Sunday, with Ferrari's Kimi Raikkonen fourth and Verstappen fifth.
New Zealander Brendon Hartley had another strong morning, completing 26 laps with the 15th best time of 20 on track.
Toro Rosso team mate Daniil Kvyat completed only six laps due to a technical problem and propped up the timesheets in last place.
Qualifying was due to start later than usual to reduce the gap between the track action and a Justin Timberlake concert at the circuit.
(Reporting by Alan Baldwin, editing by Pritha Sarkar)
