Skipper Oliver Risser remains sidelined for Swindon.
The Namibia international midfielder, missing with a thigh strain, sat out of last Wednesday's 1-0 victory at Bristol City in the competition's rescheduled first-round tie, as well as Saturday's 2-1 league defeat at Shrewsbury.
He will again watch from the stands against Saints but hopes to be fit for this weekend's visit of Rotherham. Defender Alessandro Cibocchi (ankle) remains the only other member of Paolo Di Canio's squad on the sidelines.
Alan Connell is set to come back into the Italian's matchday 18 having been dropped altogether after the memorable victory at Ashton Gate, the striker being the only change to Town's starting XI at the Greenhous Meadow.
And Di Canio is hoping for another morale-boosting victory in the Carling Cup to help raise his side after four successive league defeats.
"We want to keep positive and another win in the cup against Southampton would give us another lift going into the league at the weekend," he told Town's official website.
Richard Chaplow returns to the Southampton squad.
The midfielder has completed a three-match ban and could go straight into the starting line-up as manager Nigel Adkins shuffles his pack.
Back-up goalkeeper Bartosz Bialkowski, full-back Danny Butterfield, centre-half Aaron Martin, midfielder Morgan Schneiderlin and wingers Lee Holmes and Steve De Ridder were all handed starts in the first-round win over Torquay.
Left-back Danny Fox, the recent signing from Burnley, could make his full debut after three substitute appearances and veteran striker David Connolly is likely to be rested.
Defender Radhi Jaidi (knee) and forward Lee Barnard (ankle) are still recovering from injuries.
The winners will host either Preston or Charlton in the third round.