The two teams meet for the first time since October when they played out a 2-2 draw at Deepdale, with the Saints needing a 96th-minute own goal from Ched Evans to salvage a point.
Match preview
After suffering three successive defeats in all competitions over an eight-day period, Southampton appeared to be on course to lose again at the hands of Birmingham City last weekend as they entered half time trailing 2-1 at St Andrew's.
However, the Saints turned the thrilling contest on its head, capitalising on the dismissal of Birmingham's Dion Sanderson to march to an important 4-3 victory, with substitute Joe Aribo netting a dramatic 96th-minute winner.
Russell Martin was pleased with his side's fightback to claim a morale-boosting victory, but he is keen for Southampton to make vast improvements defensively after conceding 10 goals across their last four matches, including "three rubbish goals" shipped against Birmingham.
Nevertheless, Southampton sit fourth in the Championship table and five points behind second-placed Ipswich Town, while a title charge cannot be discounted just yet as they sit eight points adrift of leaders Leicester City, who have lost their last three league games in a row.
Although Southampton have lost their last two league matches at St Mary's, they enter Wednesday's contest unbeaten in their previous three encounters with Preston, winning their last home meeting 3-1 back in February 2009.
Since losing 2-1 at Leeds United at the end of January, Preston have put together a seven-game unbeaten run in the Championship to strengthen their hopes of securing a top-six finish in the second tier for the first time since 2008-09.
A comfortable 3-0 victory at Coventry City was followed by a goalless stalemate with sixth-placed Hull City at Deepdale last weekend, and the Lilywhites subsequently remain eighth in the table as well as three points behind the playoffs.
Ryan Lowe was left enraged after his side were not awarded a second-half penalty for a foul on Will Keane, but the Preston boss can take positives from his team keeping back-to-back clean sheets for the first time this season against two fellow playoff hopefuls.
Preston are now gearing up for a favourable-looking run of fixtures, with Wednesday's clash against an out-of-sorts Southampton side followed by five games out of six versus teams currently sitting in the bottom half of the table.
The Lilywhites will endeavour to win three away games in a row without reply for the first time since November 2020, but that could prove challenging against the Saints as they have only won one of their four encounters against the three teams that were relegated from the Premier League last season, conceding eight goals in the process.
Southampton Championship form:
W
L
W
L
L
W
Southampton form (all competitions):
L
W
L
L
L
W
Preston North End Championship form:
W
W
W
D
W
D
Team News
Southampton are still having to cope without quartet Kyle Walker-Peters, Ross Stewart (both muscle), Ryan Fraser (knee) and Juan Larios (hamstring) as they continue to recover from injury.
Taylor Harwood-Bellis could be tasked with operating at right-back once again in the absence of Walker-Peters, joining Jack Stephens, Jan Bednarek and Ryan Manning in a four-man defence.
After scoring the winner last time out, Aribo will be pushing to start in midfield ahead of either Stuart Armstrong or Will Smallbone, while a front three of David Brooks, Che Adams and Adam Armstrong is set to remain intact.
As for Preston, Kian Best is doubtful with an ankle problem, while Brad Potts remains sidelined with a hamstring injury, so Alan Browne could continue as a makeshift right wing-back.
Lowe is unlikely to make several changes, if any, to his starting lineup, with midfield duo Ben Whiteman and Ali McCann set to play just behind number 10 Mads Frokjaer-Jensen as top scorer Keane - who has 12 goals to his name this term - leads the line with Emil Riis Jakobsen.
Southampton possible starting lineup:
Bazunu; Harwood-Bellis, Stephens, Bednarek, Manning; Smallbone, Downes, S. Armstrong; Brooks, A. Armstrong, Adams
Preston North End possible starting lineup:
Woodman; Storey, Lindsay, Hughes; Browne, Whiteman, McCann, Millar; Frokjaer-Jensen; Riis, Keane
We say: Southampton 2-1 Preston North End
Considering that an average of 3.9 goals have been scored across the last seven competitive meetings between these two teams, another entertaining end-to-end contest could be on the cards on Wednesday.
Both sides will fancy their chances of claiming three precious points, but we believe Southampton, motivated by recent slip-ups from Leicester and Leeds, will find a way to come out on top on home soil.