In a repeat of the Euro 2020 final under the Wembley arch, Gareth Southgate's men could seal their place at next year's tournament should they take all three points in midweek.
A draw would also be enough to see England rubber-stamp a top-two finish in Group C - where they have amassed 13 points from a possible 15 so far - if Ukraine fail to beat basement side Malta.
The Three Lions warmed up for their Azzurri reunion by defeating Australia 1-0 in a friendly on Friday thanks to an Ollie Watkins goal, where Pickford warmed the bench as Sam Johnstone started in a second-string XI.
Ahead of his reinstatement to the starting lineup against Italy, Pickford addressed the media on Sunday and affirmed that England are not preoccupied with thoughts of payback, having gained a measure of revenge with a 2-1 win in Naples back in March.
"We know where we are in the world rankings and we know where we want to be. To do that, these are the teams you have to beat," The Independent quotes Pickford as saying.
"I don't think this game has anything to do with revenge. We went to Italy and made a bit of history, having gone so many years without beating them away from home.
"This is another tough game. They've got a new manager, played well in the last break, and we know they are a top side. This is all about qualifying for Germany. It's another hurdle we have got to get past and we'll be going for the victory."
Pickford memorably kept England's hopes of Euro 2020 glory alive by saving Jorginho's penalty in the final shootout, only for Bukayo Saka to be thwarted by Gianluigi Donnarumma as the Three Lions were left crestfallen.
However, during their inaugural Euro 2024 qualifying tie, England ended a 62-year streak without a victory on Italian soil, as Declan Rice opened the scoring before Harry Kane became the Three Lions' all-time record goalscorer.
A 10-man England side - who lost Luke Shaw to two bookable offences - held on after Mateo Retegui's equaliser for their first win in Italy since 1961, and Pickford believes that the visitors will have a greater yearning for revenge on Tuesday.
"We never really touched base on that Euro final. There was more disappointment in Qatar, getting beat in the quarters, and then coming back straight into two competitive games," Pickford added.
"That just shows you the characters we are and the type of squad and togetherness we have to beat Ukraine and then beat Italy in their own backyard in Naples in a hostile environment.
"That shows you what kind of squad we are and I think the fans love it. Every time we put the shirt on we wear it with massive amounts of pride. To beat Italy in Naples was a great feeling, but they're coming into our backyard now and they will want revenge. We just want to put on a performance, be at our best, and get a result to qualify.
"They are reigning European champions and are a top side. We only focus on ourselves. We look at what's in front of us and we will always back ourselves to beat any team because we are fully prepared and have a lot of experience and ability."
While England took a break from Group C action on Friday, Italy pummelled Malta 4-0 at the weekend thanks to a Giacomo Bonaventura strike, Domenico Berardi's brace and a late Davide Frattesi effort, cutting the gap to the Three Lions to three points in the process.