Italy throw debutant Mateo Retegui straight into the starting XI with Marco Verratti, Jorginho and Nicolò Barella in midfield against England, as Harry Kane seeks a new record.
It kicks off at the Stadio Diego Armando Maradona in Naples at 19.45 GMT.
You can follow all the build-up and action as it happens on the LIVEBLOG.
This is the opening fixture in the EURO 2024 qualifying campaign, in a group that includes Malta, North Macedonia and Ukraine.
The top two teams from each group go directly into the tournament with hosts Germany, while another three will be chosen from play-offs.
Roberto Mancini is forced to improvise due to a massive injury crisis leaving him with hardly any strikers available, so Italo-Argentine Retegui is given his Nazionale debut right from the starting XI just shy of his 24th birthday.
He has impressed at Tigre this season, on loan from Boca Juniors, scoring six goals in eight Superliga games.
Domenico Berardi and Lorenzo Pellegrini complete the trident.
Among those injured are Ciro Immobile, Federico Chiesa, Giacomo Raspadori, Ivan Provedel, Alessandro Bastoni and Federico Dimarco, while Nicolò Zaniolo is left out after his move to Galatasaray.
England also have some issues, missing Marcus Rashford, Nick Pope and Mason Mount, but Southgate opted to leave out Roma’s Tammy Abraham and Milan defender Fikayo Tomori.
Tottenham striker Harry Kane has 53 goals for England, making him joint all-time top scorer alongside Wayne Rooney, so one more and he’ll set a new record.
Kalvin Phillips has not started a single Premier League game for Manchester City this season, but surprisingly gets the nod here.
Italy: Donnarumma; Di Lorenzo, Acerbi, Toloi, Spinazzola; Barella, Jorginho, Verratti; Berardi, Retegui, Pellegrini
Italy bench: Falcone, Meret, Darmian, Gnonto, Scamacca, Pessina, Emerson, Scalvini, Cristante, Politano, Tonali, Romagnoli
England: Pickford; Walker, Maguire, Stones, Shaw; Phillips, Rice; Saka, Bellingham, Grealish; Kane
England bench: Ramsdale, Forster, Trippier, Henderson, Dier, Chilwell, James, Guehi, Gallagher, Foden, Maddison, Toney
Ref: Jovanovic (SRB)