The triple champion was a commanding 0.623 seconds quicker than his own team mate Mark Webber, next on the timesheets, in the afternoon sunshine at Monza with a fastest lap of one minute 24.453 seconds.
Ferrari's Fernando Alonso, the German's closest championship rival with a cavernous 46-point gap to make up and eight races remaining, was fifth and 0.877 off the pace on the fastest circuit on the calendar.
Last year's winner Lewis Hamilton had put Mercedes on top in the morning session with Alonso putting in the second-best lap only 0.035 seconds slower and Vettel fourth fastest.
Hamilton, who will be chasing his fifth pole position in a row on Saturday, roared around Monza's classic 'Pista Magica' in 1:25.565 on a sunny morning in the former royal park. He was sixth after lunch.
The Briton, who was booed by some of the passionate Ferrari 'tifosi' when he won for McLaren last year, had said on Thursday that he hoped they would be booing him again if it meant a return to the top step of the podium on Sunday.
The 2008 world champion certainly has a good chance, as one of only three current drivers to have won the final round of the European season and with Mercedes looking increasingly competitive.
Vettel and Alonso, the top two in the championship with Hamilton third, are the other two past winners. Alonso might have gone quicker than Hamilton in the morning had he not run wide, kicking up a cloud of dust, at the exit to the Parabolica corner on a fast lap with half an hour to go.
Hamilton's team mate Nico Rosberg was third and seventh in the two sessions while former Ferrari driver Kimi Raikkonen, the 2007 champion now with Lotus, was fifth and third equal with the same afternoon time as his own team mate Romain Grosjean.
Raikkonen suffered his first retirement of the season, ending a 27-race scoring run, at the previous race in Belgium and has fallen back to fourth in the championship behind Hamilton.
A banner in the start/finish grandstand, written in large red letters and positioned next to a Ferrari flag, declared 'Kimi in pole' in what looked like a throwback to 2007 when the Finn finished third at Monza for the Italian team.
Raikkonen has a longer wheelbase car for the race, the fastest on the calendar with speeds of up to 340kph, but has played down his chances.
"It will be very difficult," he told reporters.
"The low downforce circuits are probably not the strongest for us. Last year was difficult, and last year at Spa was quite tricky, and it wasn't easy this year either."
McLaren, with Mexican Sergio Perez and Britain's Jenson Button, were in the top 10 in both sessions.
Ferrari's Felipe Massa, whose race seat is once again in the spotlight with endless speculation about who might replace the Brazilian next year, ended the afternoon eighth fastest.
Britain's James Calado made his debut at a grand prix weekend, the newly-appointed Force India third driver taking over Adrian Sutil's car for the morning session before the German returned after lunch.
Caterham and Marussia also ran their reserve drivers, Finland's Heikki Kovalainen and Venezuelan Rodolfo Gonzalez.