This will be the 13th time these two sides have been drawn together in the last 60 years.
The Eagles met the Saints in the fourth round of the FA Cup last season, with Palace coming out on top in an exciting 3-2 victory at St Mary's. Marouane Chamakh and loanee Yaya Sanogo were on target for the boys in red and blue that afternoon.
Southampton visited Selhurst Park at the end of 2015 in the Premier League, with a Yohan Cabaye goal proving to be the difference between the two sides - and the central midfielder is back from suspension for this game and could feature.
Palace have enjoyed an impressive campaign in 2015-16, whilst Ronald Koeman's side have been struggling to replicate the incredible form they showed the previous season, but in the FA Cup it can be hard to predict the outcome, regardless of form!
Ronald Koeman: "We take this competition very seriously. After the last two defeats, we need a win for the fans, a win for ourselves.
"Graziano [Pelle] will not be involved this weekend. We hope he will be ready for next Wednesday, that will be good news."
Crystal Palace: Bakary Sako will return to the Eagles' squad, having been out of action since the home defeat to Sunderland in November and Yohan Cabaye returns from a one-game suspension.
Connor Wickham and Dwight Gayle are close to a return and should be fit for Aston Villa on Tuesday, whilst Yannick Bolasie is still some weeks off full recovery.
Southampton: Graziano Pelle will just miss this game, as Ronald Koeman confirmed, whilst Cedric Soares could be in line to return on Saturday.
Goalkeeper Fraser Forster is continuing his recovery from a lengthy knee injury, but will not feature this weekend, nor will Jay Rodriguez or Florin Gardos.
Palace have bagged a total of three goals from their last five visits to St Mary's, all of which came in last year's 3-2 FA Cup victory.
Of the last seven meetings between these two in the FA Cup, Palace have won four, drawn one and lost two.
Last month's clean sheet against the Saints was only Palace's second shut out of the south coast side in their last nine meetings. The other being a 2-0 Carling Cup win in October 2011.
Palace are the Premier LEague's most prolific team from set pieces, having scored 11 goals this term.
Lee Mason will take charge of this one, his first Emirates FA Cup of the season. He last refereed Palace during the 2-1 home defeat to Arsenal at the start of the Premier League campaign. Mason has handed out 50 yellow cards, two reds and awarded three penalties during his 16 appearances in all competitions this season.
Referee: Lee Mason
Assistant Referees: Peter Kirkup & Derek Eaton
Fourth Official: James Linington
LAST MEETING AT ST MARY'S
3rd March 2015
Southampton 1-0 Crystal Palace
Sadio Mane struck late for the Saints to secure the three points for the home side when the Eagles visited St Mary's towards the end of last season.
Alan Pardew's impressive away form, having won his opening five games on the road with Palace, was dented by Mane ending his lengthy goal drought in the 83rd minute.
This game is SOLD OUT.
Coaches will now leave from Selhurst Park at 11am, rather than 11:45am, due to roadworks on the M3. Please arrive in plenty of time to make your coach.
Live commentary of all 90 minutes from St Mary's will be available on Palace Player. Click HERE to log in or sign up.
There will also be constant updates throughout the day at @CPFC on Twitter.