The Eagles emphatically ended their run of three straight top-flight defeats with a convincing 3-1 win over Everton on Sunday.
Southampton's winless run was stretched to four following their 3-0 loss to Arsenal at the weekend.
But the Saints can go level on points with Palace with three points during their trip to south London.
Crystal Palace v Southampton: talkSPORT commentary
This Premier League clash will take place on Wednesday, December 15.
It will be held at Selhurst Park and will kick off at 7.30pm.
This game will be live and exclusive on talkSPORT 2 with coverage starting at 7:15pm.
Commentary will come from Joe Shennan and former England Women's striker Lianne Sanderson.
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Crystal Palace v Southampton: Team news
The hosts are sweating on the return of Joachim Andersen who faces a late fitness test after returning to first-team training.
However, both Nathan Ferguson and James McArthur are set to remain sidelined.
Southampton meanwhile have a number of injury concerns to contend with Adam Armstrong and Armando Broja both sustaining issues against Arsenal.
The forward pair could join Che Adams in the treatment room, leaving Ralph Hasenhuttl to turn to either Shane Long or Theo Walcott in attack.
Willy Caballero is set to remain in goal with goalkeeping duo Fraser Forster and Alex McCarthy among the other absentees alongside Stuart Armstrong.
Crystal Palace v Southampton: What has been said?
Conor Gallagher has been told to avoid making the same mistake as Jesse Lingard and quit Chelsea if they don't give him game time.
Sam Allardyce told talkSPORT: "Well I wouldn't spend too long there if I don't get into the first team.
"I'd want to come back and give it a go and I think on his form at the moment and you have to bear in mind now he made his England debut, he's an England international.
"He would want to go back and try and get in the team but I think if you do that, you've got to play enough first team games because if you don't you can easily fall backwards like Jesse Lingard."
Crystal Palace v Southampton: Match facts
Crystal Palace have lost five of their last eight Premier League home games against Southampton (W3), though they did win this exact fixture 1-0 last season.
Of teams they've faced at least 10 times in the Premier League, against no side have Southampton won a higher share of their games in the competition than they have against Crystal Palace (58% - 14/24).
Crystal Palace have won just one of their last 16 Premier League games on a Wednesday (D7 L8), while at home they're winless in 11 top-flight Wednesday games since beating Aston Villa 1-0 in February 1993.
Southampton haven't won any of their last 24 Premier League away games played on Wednesdays (D8 L16), with their last such victory coming at Chelsea in April 1995 (2-0).
Crystal Palace have only lost one of their eight home Premier League games this season (W3 D4); only Liverpool (none) have lost fewer matches on home soil in the competition this term. The Eagles are looking to win back-to-back league matches at Selhurst Park for the first time since March 2020.
Southampton have conceded a league-high 73 Premier League goals in 2021 - only four sides have ever conceded more in a single calendar year in the competition: Ipswich Town in 1994 (79), Bradford City in 2000 (76), Watford in 2017 (75) and Oldham Athletic in 1993 (74).
Conor Gallagher has been directly involved in 41% of Crystal Palace's 22 goals in the Premier League this season (six goals, three assists), the highest proportion for any team by an English player in the competition this term heading into MD17. In fact, Gallagher has either scored (four) or assisted (two) six of the Eagles' last 11 league goals (55%).
Southampton have scored 14 Premier League goals this season, but have an xG tally of 20.6. Only Norwich have a higher negative difference between expected goals (15.0) and actual goals (8) in the competition so far this term.
Southampton have lost 15 of their last 19 Premier League away games (W2 D2), with Saints conceding 50 goals and scoring just 13 in these matches.
Crystal Palace striker Christian Benteke has scored six goals in his last nine Premier League games against Southampton - only against Chelsea and Sunderland (seven each) has he scored more in the competition.