The club-record signing from Juventus is handed his debut after watching last week's goalless stalemate with Swansea City from the comfort of the bench. James Ward-Prowse is the man to make way, taking a place among the subs.
Lemina's inclusion represents Mauricio Pellegrino's only alteration from the side that started against the Swans, as Ryan Bertrand is able to take his place in the back four after recovering from a knock he picked up in that match.
The visiting Hammers, meanwhile, show four changes to the side that suffered a heavy 4-0 defeat to Manchester United last Sunday.
Southampton: Forster; Soares, Stephens, Yoshida, Bertrand; Lemina, Romeu; Davis, Tadic, Redmond; Gabbiadini
Subs: McCarthy, Long, Austin, Ward-Prowse, Boufal, Bednarek, McQueen
West Ham United: Hart; Reid, Cresswell, Fonte, Zabaleta; Rice, Arnautovic, Noble, Antonio, Ayew, Hernandez
Subs: Adrian, Obiang, Sakho, Ogbonna, Byram, Masuaku, Fernandes