That loss ended their three-game unbeaten run in the top-flight, but they now have a chance to redeem themselves against a struggling outfit from the third division.
Seventeenth in the standings with just five wins from 20 games, the Shrews have only recently found the form to navigate away from the drop zone.
They've won four times from their last five games, including wins against table-toppers Lincoln City and Hull City. They are on an eight-game unbeaten run in the league.
Steve Cotterill's side have reached this stage of the FA Cup without conceding a single goal in the competition. However, it's worth noting that they've lost 12 of their 13 FA Cup games to Premier League sides.
The match was originally scheduled for 10 January but was postponed due to an outbreak of COVID-19 in Shrewsbury Town's squad.
Southampton vs Shrewsbury Town Head-To-Head
Since Shrewsbury have never played in the Premier League before, the sides have clashed only 17 times in history. Southampton, unsurprisingly, lead the record with nine victories to Shrewsbury's four.
The upcoming clash will be their first since November 2010 when they met in the FA Cup first round.
On that occasion, the Saints went through after a dramatic 2-0 victory sealed by stoppage-time goals.
Southampton Form Guide (all competitions): L-D-D-W-L
Shrewsbury Town Form Guide (all competitions): W-W-W-D-W
Southampton vs Shrewsbury Town Team News
The home side are blighted by a raft of first-team injuries as Jannik Vestergaard is set to miss out due to a knee injury. Meanwhile, Danny Ings is likely to miss out too.
Oriol Romeu, Moussa Djenepo, Nathan Tella, Michael Obafemi, Will Smallbone, and Nathan Redmond are also on the treatment table.
Injured: Jannik Vestergaard, Oriol Romeu, Moussa Djenepo, Nathan Tella, Michael Obafemi, Will Smallbone, and Nathan Redmond.
Unavailable: Danny Ings
Several players and staff, including manager Steve Cotterill, tested positive for COVID-19 last week, so it's somewhat unclear who's available for selection.
However, Daniel Udoh is likely to start while Leon Clarke is also pushing for a starting berth.
Southampton vs Shrewsbury Town Predicted XI
Southampton (4-4-2): Fraser Forster; Yan Valery, Jack Stephens, Salisu, Jake Vokins; Stuart Armstrong, Ibrahima Diallo, James Ward-Prowse, Josh Sims; Shane Long, Dan N'Lundulu.
Shrewsbury Town (4-4-2): Harry Burgoyne; Ro-Shaun Williams, Ethan Ebanks-Landell, Aaron Pierre; Joshua Tracey, Ollie Norburn, Josh Vela, Charles Daniels; Jan Zamburek; Shaun Whalley, Daniel Udoh.
Southampton vs Shrewsbury Town Prediction
Shrewsbury will be missing some first-team players due to COVID-19, and that will make life difficult for the visitors in this match. Meanwhile, Southampton are also without several key stars.
However, the hosts still have the home advantage and enough quality in their squad to see them advance to the next round to face Arsenal.
Prediction: Southampton 2-0 Shrewsbury Town