The Brazilian was spotted in training this week, but Thomas Tuchel confirmed on Friday that he is not yet ready to feature.
Winger Christian Pulisic also misses out, with Tuchel revealing the American is struggling with muscle tightness in his calf.
“He is in a bit of a zone of risk, that’s how I understood it yesterday,” Tuchel said. “There’s a big question mark for Christian and Thiago is out.”
There was better news, however, on forward Tammy Abraham, who was forced off early in the win over Newcastle in midweek but was fit enough to train on Friday.
Tuchel also confirmed that German midfielder Kai Havertz is fit and available again, though misses out altogether.
Chelsea make four changes, one less than expected as Tammy Abraham is fit. Edouard Mendy is back in goal, joining Reece James, Kurt Zouma and N’Golo Kante in the XI.
Southampton make two changes to the side that lost to Wolves as Mohammed Salisu and Moussa Djenepo replacing injured pair Kyle Walker-Peters and Stuart Armstrong.
Southampton: McCarthy, Salisu, Bednarek, Vestergaard, Bertrand, Djenepo, Ward-Prowse, Romeu, Minamino, Ings, Redmond
Subs: Stephens, Adams, Tella, Ramsay, N'Lundulu, Forster, Ferry, Jankewitz, Chauke
Chelsea: Mendy, Azpilicueta, Zouma, Rudiger, James, Kante, Kovacic, Alonso, Mount, Werner, Abraham
Subs: Arrizabalaga, Christensen, Jorginho, Giroud, Hudson-Odoi, Chilwell, Ziyech, Gilmour, Emerson Palmieri