Joe Mason is pushing for a recall as Plymouth bid to take their relegation fight to the final day of the season.
Argyle must win to keep their hopes of survival alive and any other result will mean they drop down to League Two.
Striker Mason has been nursing an ankle injury in recent weeks but came on as a substitute in the second half of the derby defeat at Exeter on Saturday and is in the frame to start.
Midfielders Carl Fletcher, Kari Arnason and Simon Walton are all ready to play a second game in three days despite minor knocks of their own. However, midfielder Chris Clark (knee) will be sidelined again.
Striker Rory Patterson returned to the squad at Exeter after serving a one-game ban and is another option for manager Peter Reid.
Southampton will check on defender Dan Harding and midfielder Guly Do Prado ahead of the trip.
Both players were taken off as precautionary measures during the 3-0 victory at Brentford on Saturday.
“Guly came off and was feeling his leg. It was a little bit tight,” manager Nigel Adkins told the club’s official website. “Dan got a whack on his hip so we took him off too.”
Adkins could make changes for a second game in the space of three days, with Danny Butterfield, Ryan Dickson and Jonathan Forte available for recalls.
Victory at Home Park would effectively secure automatic promotion for Saints as they would go into the final game of the season three points ahead of third-placed Huddersfield with a far superior goal difference.