After being shaded by Lotus and Mercedes in the afternoon session, Red Bull regained its habitual top spot as darkness fell over Yas Marina.
Vettel had been fastest on the harder tyres in the opening quarter of an hour, and then left his switch to softs relatively late.
Lotus's Kimi Raikkonen was first to make that move and found a big time gain to go fastest.
Vettel then came through with a 1m41.335s to head Webber in a Red Bull one-two that held until the finish.
Hamilton and Raikkonen retained third and fourth places, followed by the former's team-mate Nico Rosberg.
"It's difficult to say today how we compare to the others, we know the Lotus is quick here, but we also had decent pace today," said Vettel of his day's work.
"It's not always so easy at this circuit with the conditions changing throughout the day; we start in the sun and finish at night and the track temperature changes during that time. But, no big issues, so I'm pretty happy."
Practice one pacesetter Romain Grosjean was only 12th fastest, having been sidelined by a front brake failure.
Several drivers had incidents and issues, with both Force India's Paul di Resta and McLaren's Jenson Button having to slow with punctures.
Button was still seventh, one place behind team-mate Sergio Perez, in a strong session for McLaren.
Ferrari improved on its quiet opening practice and at least got both cars into the top 10, albeit only eighth and 10th, either side of Nico Hulkenberg's Sauber.
Fernando Alonso, who had been the only man mathematically capable of making Vettel wait for the title in India, was 12th and eighth with Brazilian team mate Felipe Massa 17th and 10th.
"Compared to other Fridays, today we were a bit less competitive than usual and now we need to work out if that is down to the fact that the track characteristics do not suit our car, or if it's a question of set-up," said Alonso.
"Unfortunately, in performance terms, we are behind our rivals for second place in the constructors' classification."
Max Chilton and Giedo van der Garde both had spins, but rejoining without finding the barriers.
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