Kieran Trippier replaces Grealish in the only change from the 1-0 win over the Czech Republic last Tuesday, with Mason Mount and Phil Foden joining the Aston Villa playmaker among on the bench.
Mount and Ben Chilwell ended a week of isolation at midnight and the left-back is one of three players left out of Southgate's 23-man match-day squad, along with striker Dominic Calvert-Lewin and centre-half Ben White.
Declan Rice and Kalvin Phillips keep their places in the heart of midfield, despite fit-again Jordan Henderson playing the second half against the Czechs.
Germany start with Chelsea forward Timo Werner up front, while Bayern Munich’s Leon Goretzka comes into the midfield with Manchester City’s Ilkay Gundogan and Serge Gnabry dropping out.
England vs Germany starting lineups
England XI (3-4-3): Pickford; Walker, Stones, Maguire; Trippier, Phillips, Rice, Shaw; Saka, Sterling, Kane
Germany XI (3-4-3): Neuer, Ginter, Hummels, Rudiger, Kimmich, Goretzka, Kroos, Gosens, Havertz, Muller, Werner
Goalkeepers: Sam Johnstone, Jordan Pickford, Aaron Ramsdale*
Defenders: Ben Chilwell, Conor Coady, Reece James, Harry Maguire, Tyrone Mings, Luke Shaw, John Stones, Kieran Trippier, Kyle Walker, Ben White
Midfielders: Jude Bellingham, Jordan Henderson, Mason Mount, Kalvin Phillips, Declan Rice
Forwards: Dominic Calvert-Lewin, Phil Foden, Jack Grealish, Harry Kane, Marcus Rashford, Bukayo Saka, Jadon Sancho, Raheem Sterling
* Replaces Dean Henderson, who withdrew due to injury
Goalkeepers: Bernd Leno, Manuel Neuer, Kevin Trapp
Defenders: Matthias Ginter, Robin Gosens, Christian Gunter, Marcel Halstenberg, Mats Hummels, Lukas Klostermann, Robin Koch, Antonio Rudiger, Niklas Sule
Midfielders: Emre Can, Leon Goretzka, Ilkay Gundogan, Kai Havertz, Jonas Hofmann, Joshua Kimmich, Toni Kroos, Florian Neuhaus
Forwards: Serge Gnabry, Thomas Muller, Jamal Musiala, Timo Werner, Leroy Sane, Kevin Kolland
England’s Phil Foden will be suspended if he picks up a yellow card on Tuesday night and it’s the same for Germany quintet Matthias Ginter, Joshua Kimmich, Kai Havertz, Leroy Sané and Ilkay Gündogan.
Read our dedicated match preview here.