The Brazilian set the fastest time seen so far this week at Jerez when he broke the 1m18s barrier during a short run on soft tyres.
His 1m17.879s wasn't threatened in the afternoon, with only Nico Rosberg in the Mercedes W04 able to get within one second of the time.
Three different cars - McLaren, Lotus and now Ferrari - have topped the opening three days.
Rosberg provided a welcome relief to the setbacks Mercedes had suffered on days one and two by racking up 148 laps, comfortably the most of any driver.
The German had been forced to cut short his day one programme due to electrical issues, while a rear-brake issue caused Hamilton's debut test for Mercedes to end early and in the barriers.
Vettel also broke into triple figures in the lap count, while an afternoon improvement was enough to send him into third overall.
Kimi Raikkonen, like Vettel getting his first taste of his team's 2013 car, improved in the afternoon session and finished just over one tenth of a second down on the triple world champion.
On his first day in the Toro Rosso STR8, Jean-Eric Vergne finished fifth, just ahead of Force India's simulator driver James Rossiter.
Rossiter managed 42 laps in the morning before handing over to Paul di Resta, whose programme was then derailed after just seven laps due to an exhaust issue.
Jenson Button, who brought about a premature end to the day when he stopped out on track between Turns 7 and 8, was seventh ahead of Sauber's new signing and F1 rookie Esteban Gutierrez.
The Mexican was the day's second busiest driver with 110 laps.
Several late improvements helped carry Max Chilton into ninth, above Williams's new signing Valtteri Bottas and Caterham's Charles Pic.Today's times:
Pos Driver Team Time Laps
1. Felipe Massa Ferrari 1m17.879s 85
2. Nico Rosberg Mercedes 1m18.766s +0.887 148
3. Sebastian Vettel Red Bull 1m19.052s +1.173 102
4. Kimi Raikkonen Lotus 1m19.200s +1.321 40
5. Jean-Eric Vergne Toro Rosso 1m19.247s +1.368 85
6. James Rossiter Force India 1m19.303s +1.424 42
7. Jenson Button McLaren 1m19.603s +1.724 83
8. Esteban Gutierrez Sauber 1m19.934s +2.055 110
9. Max Chilton Marussia 1m21.269s +3.390 78
10. Valtteri Bottas Williams 1m21.575s +3.696 86
11. Charles Pic Caterham 1m22.352s +4.473 57
12. Paul di Resta Force India 1m23.729s +5.850 7