The Blades managed to return to winning ways with a 1-0 triumph over Aston Villa in midweek, while Southampton have had five days to recuperate from their dampening defeat at Everton by the same scoreline.
Not even the controversial red card brandished to Phil Jagielka could dampen Sheffield United's spirits on Wednesday evening, as the Premier League's basement boys did their fleeting chances of survival the world of good with a 1-0 triumph over Aston Villa at Bramall Lane.
David McGoldrick was on hand to lash home at the back post to propel the Blades to only their fourth league win of the campaign, and even though Chris Wilder's men had to navigate the final 30 minutes a man down after Jagielka's sending off, they held on for a memorable triumph.
The Blades' win was even more impressive when taking into account their plethora of absentees - especially in defence - so that result, and only a second Premier League clean sheet of the season, is sure to do wonders for the confidence of a depleted Sheffield United heading into the final weeks of the season.
However, that hard-fought win does not change the fact that Wilder's side are still rooted to the bottom of the table and 12 points adrift of safety - with 17th-placed Newcastle United boasting a game in hand, and it would still take nothing short of a miracle for Sheffield United to preserve their Premier League status for another year.
Since the turn of the year, the Blades have actually managed to win three of their six Premier League matches on home soil following previous triumphs over Newcastle United and West Bromwich Albion, but with their defensive ranks depleted further, Southampton will feel confident of ending their own rut this weekend.
In the midst of their own injury crisis, Southampton's previous dreams of Europe have been consigned to history and they may begin to look over their shoulder following a truly torrid run of results.
The Saints' March started in the same vein as February did - with defeat - albeit not as humiliating as their 9-0 thrashing at Old Trafford, but Ralph Hasenhuttl once again cut a frustrated figure as Everton overcame his side 1-0 at Goodison Park on Monday evening.
Richarlison's ninth-minute strike was all that separated the two sides on the day as Southampton's winless run in the Premier League extended to nine matches - eight of those ending with Southampton walking away empty-handed - with January's win over Liverpool and a 1-1 draw with Chelsea the only things that the St Mary's faithful can cheer at this moment in time.
Of course, Hasenhuttl's men are making good progress in the FA Cup and will take on Bournemouth for a semi-final spot later this month, but they are the only team in the Premier League not to have won any of their last five and the dotted line is on the horizon, with seven points now separating Southampton from the drop zone.
No English top-flight team has shipped more goals away from home than the Saints (28) so far, and Southampton have lost their last five on the road - failing to score in four of those matches - although they did ease to a 3-0 success over Sheffield United earlier in the campaign.
Sheffield United Premier League form: WLLLLW
Sheffield United form (all competitions): LWLLLW
Southampton Premier League form: LLLDLL
Southampton form (all competitions): LWLDLL
Jagielka will play no part in this one after his red card against Villa, while Wilder is also without fellow centre-backs Jack O'Connell, Chris Basham and John Egan due to injuries, and Jack Robinson is also struggling with a foot problem.
Hasenhuttl expressed concern over Moussa Djenepo after the Everton defeat as he was on the receiving end of a crunching tackle, but the winger has a chance of recovering in time for this game.
There is also optimism over Takumi Minamino, Kyle Walker-Peters and Ibrahima Diallo's potential involvement as the trio aim to shake off hamstring problems, but Theo Walcott, Oriol Romeu and Will Smallbone remain out.
Nathan Tella should feature out wide if Hasenhuttl does have to cope without three wingers, and the Southampton boss is yet to decide whether Alex McCarthy or Fraser Forster - who started against Everton - will feature in goal.
Sheffield United possible starting lineup:
Ramsdale; Ampadu, Bryan, Lowe; Baldock, Norwood, Fleck, Lundstram, Stevens; McGoldrick, McBurnie
Southampton possible starting lineup:
McCarthy; Bednarek, Vestergaard, Salisu, Bertrand; Redmond, Armstrong, Ward-Prowse, Minamino; Ings, Adams
We say: Sheffield United 1-1 Southampton
Danny Ings and Che Adams will both endeavour to take advantage of a decimated Sheffield United defence, but Southampton's goalscoring record away from home since the turn of the year is abhorrent. The Blades ought to be buoyed but also fatigued from their battling triumph over Villa, and with both sides keen to avoid any more players joining their near full-capacity treatment rooms, we are expecting a share of the spoils at Bramall Lane.
Watch the Sports Mole Football Shorts prediction for this game below: