The German, crowned world champion two races ago, edged Red Bull team-mate Mark Webber by 0.115 seconds, with Mercedes’ Nico Rosberg third from Lewis Hamilton.
Lotus’s Heikki Kovalainen was fifth, from the Saubers of Esteban Gutierrez and Nico Hulkenberg and team-mate Romain Grosjean.
“The circuit was quite slippery today,” said Vettel. “I was happy with the car, but you always know you can improve here and there.
“I think we got through the programme, [and] we were able to test some things, some were good and some not so good, but we will see. Ferrari looked quick this morning and McLaren could be a surprise here, while Lotus and Mercedes will be strong as normal.
“The track will improve now unless it rains, the car worked well on the tyres, so we’ll see what we can do on Sunday.”
Meanwhile, McLaren’s Jenson Button has been given a three-place grid penalty for ignoring red flags in the first session on Friday in Austin.
1. Sebastian Vettel Germany Red Bull-Renault 1m 37.305s (56 laps)
2. Mark Webber Australia Red Bull-Renault 1m 37.42s (54 laps)
3. Nico Rosberg Germany Mercedes-Mercedes 1m 37.785s (59 laps)
4. Lewis Hamilton Britain Mercedes-Mercedes 1m 37.958s (59 laps)
5. Heikki Kovalainen Finland Lotus-Renault 1m 38.073s (59 laps)
6. Esteban Gutiérrez Mexico Sauber-Ferrari 1m 38.229s (58 laps)
7. Nico Hülkenberg Germany Sauber-Ferrari 1m 38.254s (57 laps)
8. Romain Grosjean France Lotus-Renault 1m 38.255s (46 laps)
9. Jenson Button Britain McLaren-Mercedes 1m 38.269s (59 laps)
10. Fernando Alonso Spain Ferrari-Ferrari 1m 38.343s (49 laps) *
11. Valtteri Bottas Finland Williams-Renault 1m 38.388s (54 laps) *
12. Adrian Sutil Germany Force India-Mercedes 1m 38.719s (46 laps)
13. Felipe Massa Brazil Ferrari-Ferrari 1m 38.938s (54 laps)
14. Sergio Perez Mexico McLaren-Mercedes 1m 38.941s (48 laps)
15. Pastor Maldonado Venezuela Williams-Renault 1m 39.2s (48 laps) *
16. Daniel Ricciardo Australia STR-Ferrari 1m 39.246s (47 laps)
17. Paul di Resta Britain Force India-Mercedes 1m 39.41s (49 laps)
18. Jean-Eric Vergne France STR-Ferrari 1m 39.579s (36 laps)
19. Daniil Kvyat Russia STR-Ferrari 1m 40.065s (20 laps) *
20. Charles Pic France Caterham-Renault 1m 40.376s (58 laps)
21. Giedo van der Garde Netherlands Caterham-Renault 1m 40.563s (35 laps)
22. Alexander Rossi USA Caterham-Renault 1m 41.399s (21 laps) *
23. Max Chilton Britain Marussia-Cosworth 1m 41.605s (50 laps) *
24. Rodolfo Gonzalez Venezuela Marussia-Cosworth 1m 43.716s (17 laps) *
25. Jules Bianchi France Marussia-Cosworth 1m 47.009s (20 laps)
* Denotes time set in first practice session
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BIOGRAPHY: Ethan Hazard
BIOGRAPHY: Daniel Sturridge