Sam Johnstone, Michael Keane, Wilfried Zaha and Jesse Lingard are in Southgate's plans for the clash at Derby County's iPro Stadium, with tickets still available for the East Midlands encounter.
Johnstone is one of three goalkeepers included and has earned a recall after obtaining first-team football during a loan spell at Doncaster Rovers.
"Sam has been in our younger teams for quite a number of years now," Southgate told ManUtd.com. "At the beginning of the season, when we got together, he was injured for my first Under-21 camp and so, since then, he hadn’t really been playing first-team football.
"He’s done well at Doncaster and we felt it was a good time to bring him back into the fold really. He’s got a lot of experience within the international set-up and knows most of the boys within the team.
"We’ve got good competition with him, Jonathan Bond, Jack Butland of course, and George Long, who is playing a lot at Sheffield United. When you’ve got a group of goalkeepers like that, they work well with each other but are also striving to get the shirt."
Centre-back Keane has returned from a loan stint at Derby, hosts for the midweek fixture, and shown his class again at Under-21 level for Warren Joyce's side. Southgate does not feel his charges necessarily need to be getting first-team football in order to justify their selection.