Skipper Derry sustained a foot injury during the first half of the Eagles' 2-0 defeat at Cardiff on Saturday, with youngster James Comley coming on in his place.
Derry is already due to undergo shoulder surgery on Wednesday which is set to rule him out for up to two months, meaning his campaign could be over.
Manager Neil Warnock said: "Shaun got a nasty kick on his instep. Some studs caught him.
"I'll be very surprised if he plays after looking at his foot and there isn't really any point if he's having the operation on Wednesday."
Neil Danns failed a late fitness test on a groin injury before the Bluebirds clash and he may struggle to make it against Saints, while John Oster is still missing with a neck injury.
Southampton boss Mark Wotte has no fresh injury concerns.
Midfielder Simon Gillett is out for the season after damaging knee cartilage while player-coach Michael Svensson (Achilles), centre-back Wayne Thomas (knee), midfielder Anthony Pulis (foot) and striker Jamie White (ankle) remain long-term absentees.
However, Wotte is in defiant mood as his side aim to bounce back from the 3-0 thumping at Wolves on Good Friday.
He said: "Everybody has so much to win and so much to lose on Monday, so everybody knows that we have to play a very good game and we have to win.
"Everybody is fit from the Wolves game, and that's a good thing, but the most important thing is that they are switched on from the first second."