After missing City's 4-1 victory over Liverpool last weekend with a groin injury, Pep Guardiola revealed at his pre-match press conference that Haaland would be "ready" to play against the Saints, and the Norwegian has been thrown straight back into the first XI.
Haaland is the only change made to Guardiola's lineup, with Julian Alvarez dropping down to the substitutes' bench.
A back four of John Stones, Manuel Akanji, Ruben Dias and Nathan Ake continues to protect goalkeeper Ederson between the sticks, with Kyle Walker, Aymeric Laporte and Rico Lewis all on the bench.
Kevin De Bruyne - who is looking to register is 100th Premier League assist - starts in centre-midfield alongside Rodri and captain Iljkay Gundogan, while Haaland is joined in attack by Riyad Mahrez and Jack Grealish.
As for Southampton, Ruben Selles has made four changes from the side that lost 1-0 to West Ham United last weekend, with Romain Perraud, Duje Caleta-Car, Stuart Armstrong and Sekou Mara replaced by Ainsley Maitland-Niles, Armel Bella-Kotchap, Carlos Alcaraz and Kamaldeen Sulemana.
Alcarez will join James Ward-Prowse and former Man City youngster Romeo Lavia in centre-midfield, while Sulemana, Mohamed Elyounoussi and Theo Walcott are all set to operate in the front three.
Southampton: Bazunu; Maitland-Niles, Bella-Kotchap, Bednarek, Walker-Peters; Walcott, Lavia, Ward-Prowse, Alcaraz, Elyounoussi; Sulemana
Subs: McCarthy, Caleta-Car, Perraud, Diallo, Djenepo, S. Armstrong, Edozie, Mara, Onuachu
Manchester City: Ederson; Stones, Akanji, Dias, Ake; Gundogan, Rodri, De Bruyne; Mahrez, Haaland, Grealish
Subs: Ortega, Walker, Phillips, Laporte, Alvarez, Bernardo, Gomez, Palmer, Lewis