While Wolves have recorded just five points from six matches in the top flight, the Saints have lost five successive league fixtures.
Having witnessed their side capitulate at Manchester United last week, Southampton supporters will be realistic about their chances for the rest of the season.
Nevertheless, Ralph Hasenhuttl's side have still won three of their last eight matches in all competitions, as well as seeing luck go against them in defeats against Aston Villa and Newcastle United.
Hasenhuttl needs to address issues in the defensive third of the pitch, but the Austrian will be confident that his frontline will continue to score goals on a regular basis.
While recent arrival Takumi Minamino will play no part in this contest, the presence of the Liverpool loanee in the squad can only act as a catalyst when it comes to players upping their performance levels.
Danny Ings heads into this game having scored just once, against Premier League champions Liverpool, in his last 10 appearances.
A lack of goals has been an area of concern for Nuno Espirito Santo, although it is just one of a number of problems which Wolves have faced in recent months.
Injuries and losing their way in defence meant that claiming four points from games against Arsenal and Leicester City were regarded as a major success.
However, on the back of just two wins from 11 games against top-flight opposition, Nuno has challenged his players to finally replicate their levels of previous seasons.
Wolves have reached the last 16 of the competition with victories over Crystal Palace and Chorley, while the Saints got the better of Shrewsbury Town and Arsenal to reach this stage of the competition.
Wolverhampton Wanderers FA Cup form: WW
Wolverhampton Wanderers form (all competitions): LWDLWD
Southampton FA Cup form: WW
Southampton form (all competitions): WWLLLL
With Minamino cup-tied after his previous involvement with Liverpool, Moussa Djenepo could return for Southampton on the left flank.
Wolverhampton Wanderers possible starting lineup:
Ruddy; Dendoncker, Coady, Saiss; Semedo, Neves, Moutinho, Hoever; Vitinha; Silva, Jose
Southampton possible starting lineup:
Forster; Walker-Peters, Bednarek, Salisu, Bertrand; Redmond, Romeu, Ward-Prowse, Djenepo; Adams, Ings
We say: Wolverhampton Wanderers 1-2 Southampton
With both managers expected to make changes ahead of their league encounter at the weekend, we expect a relatively open game at Molineux. That is more likely to play into the hands of the expansive visitors, whose extra fluidity in attack could make the difference.