The likes of Jordan Pickford, Kalvin Phillips and Jordan Henderson are injured, while attackers Marcus Rashford and Jadon Sancho have been left out of the current squad.
With games against Italy and Germany still to come in the final international break before the World Cup, and some key decisions still to be made, we take a look at the team Southgate is likely to select ahead of England's first Nations League match against Italy on Friday evening.
- The Back Five -
Aaron Ramsdale will likely start in goal as the best option to replace Pickford, with the Arsenal goalkeeper starting every league game for his club this season and impressing throughout the campaign, with both his shot stopping and distribution.
While England have a plethora of right wing-backs to choose from, Reece James seems the obvious choice to start against the Italians in place of Trent Alexander-Arnold, who has struggled for form this season.
Kieran Trippier could also have a case to be in the starting eleven due to his good form at Newcastle United, and with Ben Chilwell out of the 23-man squad for Friday eveing, he could play on the opposite side of defence at left wing-back. There is also a case for Bukayo Saka, who has just been named England's 2021/22 player of the year.
The three centre backs will cause further debate, with John Stones and Marc Guehi also confirmed to be out of the squad.
That likely leaves Kyle Walker, Eric Dier and Harry Maguire as the starting back three, although many will hope that Fikayo Tomori will be given his chance.
- Midfield & Attack -
With injuries to Phillips and Henderson, it's expected that Declan Rice and Jude Bellingham will take the two central midfield spots.
One postion that goes without debate is Harry Kane's inclusion as a lone striker, with the Spurs forward only three goals behind Wayne Rooney as England's all time top scorer.
The leaves the two wingers either side of Kane, with Ivan Toney already confirmed to not be making the matchday squad at all.
Raheem Sterling netted three times at Euro 2020 and has already scored four goals in all competitions this season, putting him in contention to start against Italy.
With Jarrod Bowen, Mason Mount and Jack Grealish making slow starts to their domestic campaigns, that leaves either Saka - recently voted England's Player of the Year - or Phil Foden to fill the final spot in the starting eleven.
Considering he has just been named as the player of the year, there is a good chance Saka will start on Friday.
Although harsh on the likes of Foden and Tammy Abraham, this is our predicted side that Southgate will use against Italy.
Predicted XI: Ramsdale, James, Walker, Dier, Maguire, Trippier, Bellingham, Rice, Saka, Sterling, Kane.
