Ole Gunnar Solskjaer's men are six points from safety and will be without the injured Craig Noone, who is out for the season, for the trip to St Mary's Stadium.
Last month's 3-1 win over Fulham represents the only victory in 10 games for Ole Gunnar Solskjaer's side, which has lost three of its last four and suffered a damaging 3-0 home reverse to Crystal Palace last time out.
As a result, the Welsh team lies second-bottom of the table and six points from safety with five matches remaining.
The two teams immediately above Cardiff - Fulham and Norwich City - square off in a vital clash this weekend, meaning Solskjaer's men stand to enjoy full value from a victory on the south coast, with the prospect of the club's nearest rivals taking points off one another.
However, that looks a tall order against a Southampton side playing with a freedom allowed by a league position of eighth, and Solskjaer will have to cope without winger Craig Noone.
The 26-year-old was injured against Palace and is not expected to feature again this season.
One man definitely out for the rest of the campaign is luckless Southampton forward Jay Rodriguez, who saw his hopes of making England's World Cup squad cruelly ended when he ruptured his anterior cruciate ligament at Manchester City last weekend.
Rodriguez has scored 15 Premier League goals this season and his absence is a major blow to Southampton as the club aims to finish the season on a high note.
However, a trio of Mauricio Pochettino's players - striker Rickie Lambert, playmaker Adam Lallana and fullback Luke Shaw - remain very much in contention to gain a World Cup place.
All three impressed at the Etihad Stadium, where Southampton dominated for long periods in the first half before falling to a 4-1 defeat against Manuel Pellegrini's title chasers.
Lambert could certainly serve to cure a long-standing problem for England at major tournaments - his penalty in Manchester was his 34th successful spot kick in as many attempts.
Following a brief slump in which the club sustained three consecutive defeats in all competitions, Pochettino's team has won three of its last five matches and scored 12 times during this period.
Southampton will no doubt fancy continuing its free-scoring form as the team comes up against a Cardiff side struggling desperately to keep goals out.
Prior to the 3-0 loss against Palace, Cardiff conceded three at West Brom and six at home to Liverpool, although the team did at least score three goals in each of those games.
It remains to be seen whether goalkeeper Artur Boruc (back) and forward Gaston Ramirez (ankle) will feature for Southampton after both men missed the game against City.