Ledley pulled out of Wales' friendly with Luxembourg with a hamstring injury - the same problem which kept him sidelined for a month only recently.
The winger is expected to be okay to face Saints but with the FA Cup semi-final against Barnsley just a week away, Jones is likely to adopt a cautious approach with one of his prized assets.
Striker Jimmy Floyd Hasselbaink serves the second match of a three-game ban for his recent red card and defender Kevin McNaughton could again miss out with a hamstring problem.
Warren Feeney, Trevor Sinclair and Aaron Ramsey will all hope to make the starting line-up after being named as substitutes in last week's win over Bristol City.
Jones revealed this week that Robbie Fowler is "progressing well" with his hip problem, however a return date for the striker is yet to be established.
Chris Perry goes straight into the Southampton squad for the trip.
The veteran former Wimbledon and Tottenham centre-half has been drafted in for the relegation run-in after joining on loan from League One side Luton.
Wayne Thomas and Darren Powell should start at the back with Perry providing cover on the bench after Andrew Davies was ruled out for the season with a fractured cheekbone.
Ian Pearce has gone back to Fulham following an injury-hit loan spell and a third centre-back, club captain Claus Lundekvam, was this week forced to retire.
Richard Wright should keep his place in goal after a clean sheet in the draw with Coventry on his debut, although Kelvin Davis (dislocated finger) was fit enough to be on the bench.
Midfielder Inigo Idiakez is close to a return from a hamstring injury.