Gunners head coach Mikel Arteta has made three changes to the side that defeated Paris Saint-Germain 2-0 in the Champions League in midweek, and Sterling is one of two alterations in the final third.
The 29-year-old has replaced Gabriel Martinelli on the left flank, while Gabriel Jesus will seemingly operate through the middle, as Leandro Trossard also drops down to the substitutes' bench.
Sterling's former Chelsea teammate Jorginho is the third new player to be introduced into the Arsenal XI, and the experienced midfielder has benefitted from Arsenal's full-back crisis to join Declan Rice and Kai Havertz in the middle.
With Jorginho, Rice and Havertz manning the engine room, Thomas Partey is set to start on the right-hand side of defence, with neither Ben White nor Jurrien Timber fit enough to take part.
Takehiro Tomiyasu has made the bench for the hosts after recovering from a knee problem, but the Japan international - who is yet to make a single senior appearance this season - is not deemed ready to start.
Aaron Ramsdale starts as Southampton play it safe
Following his midweek debut, Mikel Merino is also on the bench again, as are academy trio Ethan Nwaneri, Myles Lewis-Skelly and Nathan Butler-Oyedeji.
Meanwhile, Southampton boss Russell Martin has made four alterations from the side that lost 3-1 to Bournemouth on Monday, and the Saints will seemingly change formation for the clash with the Gunners.
Martin has opted to bring in an extra defender in Ryan Manning, who makes his first senior appearance of the season and looks likely to operate in a three-man central defence with Taylor Harwood-Bellis and Jan Bednarek.
The trio will protect ex-Arsenal goalkeeper Aaron Ramsdale as Manning takes the place of Chelsea-owned midfielder Lesley Ugochukwu, while Kyle Walker-Peters comes in for Charlie Taylor on the left.
Ugochukwu was one of three players taken off at half time in the Bournemouth loss - the others being Maxwel Cornet and Ryan Fraser - and both attackers have also lost their place in the visitors' starting lineup.
Instead, Joe Aribo joins Flynn Downes in the engine room, while Ross Stewart makes his full Premier League debut up front with support from Mateus Fernandes and Tyler Dibling.
Arsenal starting lineup: Raya; Partey, Saliba, Gabriel, Calafiori; Havertz, Jorginho, Rice; Saka, Jesus, Sterling
Subs: Neto, Lewis-Skelly, Tomiyasu, Kiwior, Merino, Nwaneri, Martinelli, Trossard, Butler-Oyedeji
Southampton starting lineup: Ramsdale; Sugawara, Harwood-Bellis, Bednarek, Manning, Walker-Peters; Downes, Aribo; Fernandes, Dibling; Stewart
Subs: McCarthy; Taylor, Bree, Ugochukwu, Lallana, Archer, Brereton Diaz, Armstrong, Onuachu