The 23-year-old German triumphed for tiny Toro Rosso at the Milanese circuit in 2008, after also securing his first pole, and Sunday's final European race of the season promises to be another big challenge despite Red Bull's qualifying prowess.
Red Bull Racing boss Christian Horner expects Monza, the fastest circuit on the calendar with its long straights, to again favour McLaren [ Images ] and be his championship-leading team's hardest race of the year.
Vettel arrives at the historic track with criticism ringing in his ears after he drove into McLaren's world champion Jenson Button [ Images ] at Spa, shunting the Briton out of a race that he also failed to take any points from.
The German, who has taken seven poles in 13 races, is third overall and 31 points off McLaren's overall leader Lewis Hamilton [ Images ] with six races remaining.
Vettel needs a good result to stay in contention, with Australian team mate Mark Webber [ Images ] in the form of his life and now 28 points ahead.
"In Hungary I was asleep during the safety car period and made an error. And in Spa, when I lost the car while overtaking Jenson Button I make a mistake too. But I am open and honest enough to admit that," the German, who apologised to Button after Belgium, said last week.
"During the first 13 races, it did not all go smoothly but I am still only 31 points behind."
Hamilton has never won at Monza, the temple of Italian motorsport with its wooded surroundings and ancient banking so evocative of past glories, but will be a favourite after a victory at Spa that sent him three points clear of Webber.
The 25-year-old Briton started on pole in Italy [ Images ] last year but crashed out on the last lap while in third place.
Having won the three other most historic races on the calendar -- Britain, Belgium and Monaco -- a Monza triumph would complete a classic collection for Formula One's youngest champion.
"We've generally always been very, very good in Monza. The straights will be good for us there," Hamilton told Reuters after Spa. "Hopefully our package is strong there.
"It's a very historic circuit, it's Ferrari's [ Images ] back garden as well so it's one you want to win even more. But also we have really great fans in Italy, even though it's Ferrari country," he added.
"You want to win every grand prix but there are certain ones that mean a lot more to you. Whilst Abu Dhabi is a great grand prix, it doesn't have the same history as Monza. So Monza has a little bit more significance."
Webber, second at Spa, has never finished higher than seventh in eight starts at Monza but he has also never before had a car like this year's Red Bull.
Sunday will also be double world champion Fernando Alonso's [ Images ] home debut for Ferrari, who faced the possibility of heavy sanctions after being summoned to appear in front of the governing body in Paris on Wednesday.
Alonso, a winner at Monza with McLaren in 2007 when Hamilton was runner-up, is currently fifth overall and 41 points adrift of his former team mate.