Kalidou Koulibaly is back from suspension and goes straight into the line-up.
There is also a return to the defence for skipper Cesar Azpilicueta who makes his 450th Chelsea start and with Conor Gallagher now suspended, Thomas Tuchel makes three changes.
Up front, there is a start for Hakim Ziyech. Kai Havertz and Raheem Sterling retain their places.
There is no Reece James due to illness. Trevoh Chalobah has joined N’Golo Kante on the injured list.
Billy Gilmour and Harvey Vale are on the bench for the first time this season.
Southampton make two changes from their home defeat by Man United at the weekend, with Romain Perraud and Ibrahima Diallo coming in.
Chelsea: Mendy; Azpilicueta (c), Thiago Silva, Koulibaly, Cucurella, Loftus-Cheek, Jorginho, Mount, Ziyech, Havertz, Sterling.
Subs: Kepa, Chilwell, Ampadu, Chukwuemeka, Gilmour, Kovacic, Pulisic, Vale, Broja.
Southampton: Bazunu; Walker-Peters, Bella-Kotchap, Salisu, Perraud, Ward-Prowse (c), Lavia, Diallo, Elyounoussi, Adams, A Armstrong.
Subs: McCarthy, Lyanco, Bednarek, Aribo, Valery, S Armstrong, Djenepo, Walcott, Mara.
The referee is Michael Oliver.