Christian Benteke and Wilfried Zaha were both on target at Stamford Bridge as Palace stunned leaders Chelsea at Stamford Bridge on Saturday and Sam Allardyce will be hopeful his key players can replicate such impressive performances on the South Coast.
The Eagles are currently four points clear of the relegation zone but cannot consider themselves safe with a difficult run-in on the horizon.
However, Claude Puel's side have won just two of their last eight top-flight fixtures and the south Londoners will be confident they can make it five wins on the bounce to boost their survival hopes even further.
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Southampton host Crystal Palace at St. Mary's Stadium with kick-off scheduled for 7.45pm on Wednesday, April 5.
TV AND LIVE ONLINE COVERAGE
The match will be not be televised live on TV in the UK. Alternatively, you can follow all the build-up and action from 6.45pm with Standard Sport’s London Football live blog.
Allardyce is unlikely to make too many changes, having seen his players deliver so emphatically against the league leaders.
The Eagles' defence has conceded just one goal in five games but Palace will be forced into a reshuffle at the back due to injuries to Scott Dann (knee) and James Tomkins (calf).
Patrick van Aanholt and Mathieu Flamini are rated as doubtful while James McArthur could recover from a back spasm problem.
Southampton are also facing a selection headache in defence with Virgil van Dijk sidelined with an ankle problem.
Manolo Gabbiadini is suffering with a groin strain and is also out.
Shane Long and Jay Rodriguez will deputise up front as the Saints go in search of a first win on home turf since late January.
Southampton starting XI: Forster, Soares, Stephens, Yoshida, Bertrand, Davis, Romeu, Ward-Prowse, Tadic, Redmond, Rodriguez.
Crystal Palace starting XI: Hennessey, Ward, Delaney, Sakho, Schlupp, Milivojevic, Cabaye, Zaha, Puncheon, Townsend, Benteke.
BETTING ODDS (via 888 Sport)
Southampton to win: 41/50
Crystal Palace to win: 37/10