The Manchester United man has battled his way back from an ankle problem and is training with the England squad, but the weekend will likely come too soon for him, leaving Southgate in a predicament at the back.
Despite going with a four-man rearguard against Romania, Southgate is understood to be trialling a three-man defence with Luke Shaw alongside John Stones and Kyle Walker, which would see Tyrone Mings drop out following his shaky showing last weekend.
Trent Alexander-Arnold's injury leaves Kieran Trippier and Reece James in direct competition for the right-wing back spot, and the Atletico Madrid man is reportedly in line to get the nod, while Ben Chilwell is a shoo-in on the left if Shaw features further back.
Jordan Henderson may not be deemed ready to start just yet either, so a two-man midfield of Declan Rice and Kalvin Phillips appears the most likely option for the Three Lions, with Jude Bellingham patiently waiting in the wings.
The final third of the field is where the bulk of Southgate's dilemmas lie, as the England boss must choose two of a plethora of talented attackers to provide support to Premier League Golden Boot winner Harry Kane.
Jack Grealish's strong showings earlier this month could see him rewarded with a place over Marcus Rashford and Bukayo Saka - the latter of whom is doubtful with a hip issue anyway - and Champions League winner Mason Mount will hope to edge out Phil Foden, Jadon Sancho and Raheem Sterling.
England possible starting lineup: Pickford; Walker, Stones, Shaw; Trippier, Rice, Phillips, Chilwell; Mount, Grealish; Kane