Town, without manager Steve Cotterill who continues his recovery from Covid-19 in hospital, gave a tireless and brave display at St Mary's but an early goal from young Saints forward Daniel N'Lundulu was added to by James Ward-Prowse's free-kick in the closing stages.
We discuss the talking points on the strange evening in which Town ended exactly three weeks without a fixture – without their supporters or manager in attendance.
1. Impressive debuts
Loan signings Matthew Pennington and Harry Chapman were thrown straight in for their blue and amber bows after merely a handful of training sessions with their new team-mates.
The pair, on loan from Everton and Blackburn respectively, both caught the eye at opposing ends of the pitch at St Mary's.
Stopper Pennington, 26, grew into the game well and was assured at the back. He used his powerful frame well to deal with the likes of Shane Long and was not afraid to make runs forward out of defence with the ball.
Attacker Chapman, 23, impressed from the off in the advanced midfield No.10 role. Immediately he showed a willingness to drive with the ball and ability to turn defenders. He was also keen to let fly from distance and Town fans always value a shoot-on-sight approach.
Both enjoyed impressive debuts, hopefully – from Shrews' perspective – the start of things to come, with midfielder David Davis to also add into the mix.
2. Defensive prowess
It feels like a lifetime ago given everything that has gone on since, but Town's form just before Christmas was immense, with three clean sheets and victories on the spin at top four opposition.
There were no signs that the enforced three-week break had done anything to unhinge Shrewsbury's impressive backline at St Mary's on Tuesday.
Pennington slotted in on the right of the visitors' central back three – with Ro-Shaun Williams shifted out to right wing-back – and the four defenders were as hard as nails.
Their only real lapse in concentration came early on as N'Lundulu punished some ball-watching with a neat finish – although controversial for a possible handball.
But some of Town's defending, particularly in the second period, was a joy to behold. Ethan Ebanks-Landell and Williams made some fine interceptions and Pierre gave a monstrous display with two supreme goalline clearances. His display will have impressed onlookers Championship suitors.
3. Wing-back worries
In the space of a few hours it was confirmed that both Matt Millar and Charlie Daniels – along with Marc Pugh – had left the club as their loan and short-term deals ended.
Millar and Daniels were both regulars under Sam Ricketts, who brought them to the club, and Cotterill, in the wing-back positions.
The duo were pivotal parts in the stunning turnaround under Cotterill. Aussie loanee Millar became an immediate fans' favourite with two goals in his first four appearances and powerful, willing charges down the right flank.
Experienced campaigner Daniels grew with every game and had become a real key part of Town's unit. His ability on the ball shone through in League One fixtures.
Scott Golbourne made a rare start on the left at Southampton and was given a tough time by Yan Valery. Williams was shunted out to the opposite flank and while willing isn't a natural attacking full-back. Cotterill and his team must make replacing their effective and influential wing-back pair a transfer priority over the next 10 days or so.
4. Fitness boosts
More substitutes can be named in the FA Cup this season but, regardless, of the rule change, it was still a slightly unexpected delight to see the return of a few long-term absentees in the Town ranks.
Included among the matchday 20 were Rekeil Pyke, Ryan Sears and Sean Goss. The former pair had not kicked a ball in anger since September owing to injury.
They both emerged from the bench late on at St Mary's as Town pushed for an equaliser. While remiss to suggest they will instantly challenge for a place in Shrewsbury's first XI, their availability in the matchday squad provides the staff with more options.
Pyke played just three games before his long-term quad injury, he netted on an impressive debut at Middlesbrough and will want to make up for lost time, whereas Sears has only sampled one half of EFL Trophy action this term.
Goss has not played since the win at Lincoln in December through injury and, having enjoyed a renaissance under Cotterill, will want to continue. The comebacks mean only Brad Walker remains sidelined with injury from the first-team squad.
Meanwhile, it was Dave Edwards' 600th career appearance - a fantastic feat for the midfielder.
5. Work rate
Wilbraham was keen to note post-match just how Shrewsbury were unwilling to use their period of enforced isolation as an excuse.
It is only expected that Town's fitness levels will have dropped off significantly given all players have been isolating – and indeed, many testing positive for the virus.
They may have been away from Sundorne Castle for the best part of a fortnight, losing key match sharpness, but you would not know that watching on Tuesday night. Josh Vela in particular was everywhere, Shaun Whalley and Daniel Udoh too were tireless.
The visitors might have been a little shell-shocked in the opening stages but they soon got to grips with their high-flying top flight hosts and ran them toe-to-toe right until the death.
Town tired as the second half went on – it would be a huge shock if they had out-ran their hosts all evening – but the effort and application given the time away bodes well for Sunderland on Saturday and beyond.
6. Records let slip
Ultimately, it was not quite meant to be.
It felt as if the fairytale narrative may have been on the visitors' side as they went into battle with their illustrious hosts without their leader on the touchline.
But Town's long-standing 135-year run of not winning away at top flight opposition in the famous old competition goes on. It is quite some stat given Shrewsbury's proud FA Cup pedigree, featuring recent runs and the efforts of the early 1980's and mid-to-late 1960's.
Salop were also unable to make it a hat-trick of runs to the fourth round for only the second time ever and the first time since a run of of four consecutive years between 1980 and 1984 – albeit second tier Town entered at the third round stage then.
7. League matters
It will be a trip to the north east and the Stadium of Light for Shrewsbury on Saturday, rather than a lucrative televised Saturday lunchtime fourth round contest against Arsenal.
There, Salop will hope to inflict further home misery on the Black Cats after Plymouth beat them at home in the week.
But many of a blue and amber persuasion will be relieved, in a way, to be back to the bread and butter of League One action.
Despite no league action since that Blackpool victory on December 28, Town have only missed two league games, against Crewe and Lincoln, with FA Cup action taking place too.
Mercifully, they haven't lost much ground. Cotterill's men still find themselves in 17th in League One, albeit the gap to the bottom four has now been cut from five points to just three.
Shrews do, however, now boast up to two games in hand over a number of their rivals. That is all well and good, but points on the board matter most, and fans will be hoping that momentum from before the breakout has not gone away. If the Southampton display was anything to go by, they will be fine.