Lewis Hamilton once again proved unstoppable in Austin, Texas as he topped the practice timesheets for a second time at the Circuit of The Americas.
Hamilton, chasing a fifth US win in six years and one that could seal a fourth World Championship crown, beat his own track record with a best time of 1:34.668.
Max Verstappen, in P2, closed to within four tenths, with Vettel, in P3, half a second off the pace and only setting his first timed lap 45 minutes into the session due to a late start and a big spin off at the penultimate corner.
Hamilton's team-mate Valtteri Bottas was a further tenth back in P4, with Daniel Ricciardo and Kimi Raikkonen rounding off the top six.
The grey, murky backdrop that lingered throughout FP1 made way for blue skies and a dry track in the afternoon, producing a much more meaningful session ahead of Sunday's race.
As the Red Bull duo of Ricciardo and Verstappen traded top spot in the opening stages, Vettel, the last driver to head out of the garage, made only a brief appearance to begin with as he lost control at the penultimate corner on his first hot lap and found the gravel trap.
After a brief lull in proceedings, the drivers began to slowly emerge from the garages again with plenty of the pink ultrasofts on display.
Hamilton, who had a scruffy start to the FP2 session, suddenly came to life by setting a 1:34.668 which surpassed the previous track record that the Brit set himself in Q3 at the Circuit of The Americas last year.
Similar to FP1, nobody else could really get close to Hamilton's best time with Verstappen four tenths down and Vettel finding himself half a second behind again – only setting his first timed lap at the halfway point of the session.
Attention then turned to the longer race programmes, but not for Vettel, who required yet another set-up change and was unable to get into any sort of rhythm throughout the afternoon.
Vettel reported "something weird with the front axle" on the way back to the garage and said the car "felt like jelly", losing more valuable track time as a result.
Team-mate Raikkonen, though, had the best lap average on the ultrasofts during the race simulation runs with a 1:40.7, three tenths quicker than Mercedes and Red Bull.
1 Lewis Hamilton Mercedes 1:34.668 – US
2 Max Verstappen Red Bull 1:35.065 0.397 US
3 Sebastian Vettel Ferrari 1:35.192 0.524 US
4 Valtteri Bottas Mercedes 1:35.279 0.611 US
5 Daniel Ricciardo Red Bull 1:35.463 0.795 US
6 Kimi Raikkonen Ferrari 1:35.514 0.846 US
7 Fernando Alonso McLaren 1:36.304 1.636 US
8 Felipe Massa Williams 1:36.460 1.792 US
9 Sergio Perez Force India 1:36.481 1.813 US
10 Esteban Ocon Force India 1:36.490 1.822 US
11 Carlos Sainz Renault Sport 1:36.529 1.861 US
12 Nico Hulkenberg Renault Sport 1:36.534 1.866 US
13 Daniil Kvyat Toro Rosso 1:36.761 2.093 US
14 Kevin Magnussen Haas 1:37.285 2.617 US
15 Stoffel Vandoorne McLaren 1:37.463 2.795 US
16 Lance Stroll Williams 1:37.788 3.12 US
17 Brendon Hartley Toro Rosso 1:37.987 3.319 US
18 Pascal Wehrlein Sauber 1:38.165 3.497 US
19 Marcus Ericsson Sauber 1:38.262 3.594 US
20 Romain Grosjean Haas 1:38.387 3.719 SS