With the Three Lions in control of Group I, they travel to the Pyrenees to face Andorra on October 9 before hosting Hungary at Wembley three days later.
For the September triple-header, Southgate stuck with the majority of the squad which took England to the final of Euro 2020 earlier in the summer.
There will have to be changes this time around with Manchester United skipper Harry Maguire likely to miss out with a calf problem and Trent Alexander-Arnold suffering an adductor injury in
Liverpool training earlier this week.
While Southgate has plenty of options in defence, those injuries could present an opportunity for the likes of Ben White, Fikayo Tomori or Joe Gomez to earn recalls.
White is the most likely, having settled into life at Arsenal after being included in the squad at the European Championship as a late replacement for Alexander-Arnold.
With the Liverpool right-back missing once more – and concerns over the severity of an ankle injury to Chelsea's Reece James – Southgate may be tempted to take a look at a number of uncapped full-backs including Aaron Wan-Bissaka, Tino Livramento or Max Aarons.
One player almost certain to return is Manchester City's Phil Foden, who missed the recent games with Hungary, Andorra and Poland due to a foot complaint.
It remains to be seen, however, if Manchester United's Mason Greenwood will earn a call-up.
The 19-year-old has one senior cap but was left out in September despite scoring in United's opening three Premier League fixtures of the new campaign with Southgate saying Greenwood was "in his thoughts" but that he was conscious that progression into a senior England player came at the right time.
Instead, Leeds striker Patrick Bamford was included as the only new face but he struggled on his debut and has hit just one goal in six club appearances this season.
If Southgate wants to continue auditioning understudies for Harry Kane, Brentford's Ivan Toney may have a sniff of being involved following his fine start.
Toney has two goals and two assists so far for the Bees and has played a big part in their impressive Premier League introduction.
Kane himself will be included despite failing to find the back of the net in the Premier League for Tottenham so far this season.
He scored three in three during the last international break and is now three behind the 44 England goals scored by Jimmy Greaves – who died earlier this month.
The home fixture against Hungary will be an emotional one with tributes to both Greaves and fellow 1966 World Cup winner Roger Hunt, who died this week, with the Football Association finalising plans on how the two players will be remembered.