The Three Lions will be visitors to Swansea City’s Liberty Stadium for the game as they look to close in on securing top spot in their group on the road to Czech Republic 2015.
And even though Southgate is set to name a large squad for the trip, with the Toulon Tournament in France following swiftly on from the clash with Wales, he could be without a few of his regulars due to club commitments at the end of the season.
Wales v England
UEFA European U21 Championship
Qualifying Group 1
7.30pm, Monday 19 May
Liberty Stadium, Swansea City FC
Call 0844 815 6665 for tickets
"I think we’ve got a few scenarios, as there are some players who may not be with us,” said Southgate, whose initial squad will be shortened for Toulon after the Wales game due to age restrictions in that tournament.
"Because of The FA Cup Final, it’s likely that Carl Jenkinson won’t be available and it’s the play-off final in the week that we meet up.
"We’ve also got the U19s playing later this month and it’s key for us that they get the opportunity to qualify for their European Championships, so we have prioritised that and we won’t take any of their group.
"So it’s an interesting challenge for us this summer. We think there are some exciting players coming through and we’re in a good position in our qualifying group, but we know the Wales game will be very tough and it’s a derby."
The teams met as recently as March, when a Nathan Redmond goal proved enough to earn England a 1-0 win in Derby.
Watch highlights from the game with Wales at Derby
And after seeing Wales at close quarters on that occasion, Southgate is expecting a real test for his players at the Liberty Stadium.
They will meet up at St. George’s Park on Thursday 14 May to start their preparations before travelling to South Wales a few days later.
"We’ve got to make sure that we get it right," added the former Middlesbrough manager.
"I think it’s a good game for us and I think Wales will be buoyed by the performance they put in at Derby in March.
"They’ll recognise that we’re a few players missing, so will be after a scalp."
England fans can attend the game at the Liberty Stadium on Monday 19 May, with tickets priced at just £5 for adults and £2 for concessions. Call 0844 815 6665 to buy your tickets.
