Dan Harding has a chance of being fit for Southampton.
The left-back has been nursing a groin problem but could return to the squad after he was close to being included against Brighton on Saturday.
Winger Alex Chamberlain is unlikely to recover from an ankle injury in time, while Lee Barnard will remain on the sidelines.
The 16-goal striker was taken to hospital with an ankle injury during the victory over Bristol Rovers and could struggle to play again this season.
Adam Lallana has been struggling with a groin tear lately but came on as a half-time substitute during the win over newly-crowned champions Brighton and could be restored to the starting line-up.
First-team coach Mick Wadsworth is set to again ring the changes for Hartlepool.
Wadsworth opted to hand three players – Darren Holden, Andy Rafferty and Josh Rafferty – debuts in Friday’s 1-1 draw with Tranmere.
But, despite the trio impressing, they are unlikely to line-up at St Mary’s, much like striker Michael Mackay who was handed his first start of the campaign against Rovers.
That could pave the way for Scott Flinders, Steve Haslam, Evan Horwood and Ritchie Humphreys to come back into the starting line-up.
Right-back Neil Austin and striker James Brown have lined up for the reserves recently, but this game is likely to come too soon.
Pools are currently 14th in League One and, with safety assured, are already building towards next season.