Goalkeeper Mendy picked up an injury while on international duty with Senegal, and Lampard has decided to start Kepa Arrizabalaga over Willy Caballero in goal.
Silva is not injured but has been left out of the squad after making the mammoth round-trip to Peru for Brazil’s World Cup qualifier on Wednesday night.
However, there is some good news for Lampard as wingers Christian Pulisic and Hakim Ziyech return to the squad, with the former starting.
Pulisic has not started a game since going off injured in last season’s FA Cup final defeat to Arsenal, while Ziyech is yet to make his debut after arriving from Ajax in the summer.
Ben Chilwell is back in the Chelsea lineup despite withdrawing early from international duty with England.
The left-back missed England’s friendly against Wales because of a coronavirus breach and was released from the squad prior to Wednesday night’s 1-0 defeat to Denmark, in order to return to Cobham and build fitness ahead of the Saints clash.
Chelsea XI: Arrizabalaga, Azpilicueta, Christensen, Zouma, Chilwell, Kante, Jorginho, Pulisic, Havertz, Mount, Werner.
Subs: Abraham, Caballero, Tomori, Giroud, Hudson-Odoi, Ziyech, James.
Southampton XI: McCarthy, Walker-Peters, Bednarek, Vestergaard, Bertrand, Walcott, Ward-Prowse, Romeu, Redmond, Adams, Ings
Subs: Stephens, Long, Obafemi, Valery, Tella, Diallo, Forster
Referee: Robert Jones