It kicks off at 19.45 UK time (18.45 GMT) at San Siro.
This is a very balanced group going into the penultimate round, as Hungary are the surprise on top with six points, followed by Germany on five, Italy four and England two.
Whoever finishes last will be relegated into Nations League B, so this is potentially crucial for both sides who battled it out for the EURO 2020 Final just over a year ago.
Ciro Immobile was the latest addition to the absentee list, along with the likes of Marco Verratti, Matteo Politano, Lorenzo Pellegrini, Sandro Tonali, Domenico Berardi, Lorenzo Insigne, Federico Chiesa, Alessandro Florenzi, Manuel Locatelli, Leonardo Spinazzola and more.
It is a shift from the usual 4-3-3 approach that has struggled to score goals lately, but also mirrors the 3-5-2 used by Gareth Southgate.
England are preparing for the 2022 World Cup, but Kalvin Phillips, Jordan Henderson, Ivan Toney, Ben Chilwell, Marc Guehi and suspended John Stones are out, so 19-year-old Borussia Dortmund talent Jude Bellingham steps into the XI.
Harry Maguire is chosen, despite not starting a Premier League game at Manchester United for the last six weeks, as the defender has been dropped.
England are without a win in four matches and have not beaten the Azzurri on Italian soil since 1961.
The final games in this group are England-Germany and Hungary-Italy on Monday.
Italy: Donnarumma; Toloi, Bonucci, Acerbi; Di Lorenzo, Barella, Jorginho, Cristante, Dimarco; Scamacca, Raspadori
England: Pope; Maguire, Dier, Walker; James, Bellingham, Rice, Saka; Sterling, Kane, Foden
England bench: Ramsdale, Henderson, Trippier, Shaw, Grealish, Coady, Ward-Prowse, Tomori, Mount, Bowen, Alexander-Arnold, Abraham
Ref: Manzano (ESP)