Joe Gomez has added to Jurgen Klopp's defensive woes at Liverpool.
The centre-back suffered a knee during England training on Wednesday.
He'll return to Liverpool to have the injury fully assessed before the duration of his absence is ascertained.
Gomez will miss all of England's games in the international window, including the friendly with the Republic of Ireland.
However, it's feared the 23-year old will also miss a substantial portion of Liverpool's season.
"I can't tell you how serious it is because [Gomez] is yet to have scans," Southgate told his pre-match press conference.
"What was upsetting to see, he was in a fair bit of pain. There was nobody around him when the injury happened. I didn't like that element of it.
"But we've just got to wait and see what the scans show. We're all hopeful for him that it's not what it might be.
"But it's not a good situation. I don't see him being involved in the games with us, that's for sure.
"We're hoping and praying it is not going to be a long-term one. We'll just have to see."
The Premier League champions are down to the bare bones at the back, with Virgil van Dijk a long-term absentee with a knee ligament injury.
It leaves Joe Matip as their only fit, recognised, senior centre-back. Fabinho has filled in there recently, but the Brazilian is working through a thigh injury.
Nat Phillips started last month's 2-1 Premier League win over West Ham, while 19-year old Rhys Williams partnered Gomez in the 5-0 win away to Atalanta in the Champions League.