Vettel, who won at Monza in 2011, was 0.623 seconds faster than Webber and looked in complete control from the start of the afternoon session. It is an ominous sign for his rivals ahead of Sunday's race.
"It was a good day, that's for sure, but we've got our feet on the ground," Vettel said. "It's still only a Friday. I don't know, maybe the others had some problems. But regarding ourselves, it was a good day, I didn't have any issues with the car, it felt pretty comfortable.
"I'm sure it will be very tight, as we saw in first practice. Second practice, if you look at it too much, is a bit of a distraction. I think it will be close tomorrow in qualifying, with many cars in a couple of hundredths. Sure today was positive, but it's a long weekend. We'll see what we can improve for tomorrow."
The three-time defending champion leads second-placed Fernando Alonso by an intimidating 46 points in the standings.
Red Bull has not achieved the best results at Monza, and Vettel's win two years ago is its only podium position since 2005. However, the German looked in impressive form and could be on course for a fourth victory of 2013.
Kimi Raikkonen was third in glorious conditions at Monza, 0.663 seconds behind Vettel, with the same time as Lotus teammate Romain Grosjean.
Alonso, Lewis Hamilton, Nico Rosberg, Felipe Massa, Jenson Button and Sergio Perez completed the top 10 with little more than half a second between Perez, in 10th, and Webber.
Hamilton, who won at Monza last year, was fastest in the morning session, 0.035 seconds better than Alonso, with Vettel fourth quickest, 0.188 seconds slower.
Rosberg was third, 0.139 seconds slower than his Mercedes teammate. Hamilton has qualified in pole position in the past four races, while his team has done so in eight of the past nine.
The field was more tightly packed at a high-speed Monza track in the morning, with less than half a second separating Hamilton from Button in seventh. There was less than a second gap between the top 14, with Massa only 0.884 seconds slower than Hamilton.
Massa, however, is under investigation after appearing to ignore a red light at the end of the pitlane during the first practice. The Brazilian stopped beyond the line after the light had come on to indicate the end of the session.
Massa and Ferrari were summoned by the stewards for an explanation but a later statement by officials announced that the hearing has been delayed pending additional information.