This competition provides a welcome respite to the inconsistencies of a frustrating maiden Premier League campaign for Claude Puel's Saints, having lost their last three top-flight games to end 2016 and start 2017 in disappointing fashion.
Meanwhile, Liverpool - as the most successful team in the League Cup on eight triumphs - are at this stage for the third successive season and only lost out on penalties to Manchester City in the final last term, just four months into Jürgen Klopp's Anfield tenure.
The Reds have fielded largely second-string sides so far this term on their way past Burton Albion, Derby County, Tottenham Hotspur and most recently Leeds United - but have looked impressive on their route to the final four.
Southampton too have utilised their depth in the EFL Cup. No side has used more players than them (25) this season, although that hasn't prevented them disposing of Premier League opposition in every round, beating Crystal Palace, Sunderland and Arsenal.
They have played one less round than Liverpool due to their European commitments earlier in the campaign, but are fully worthy of their first semi-final berth since 1987 and only their third ever.
Yet they have never won the competition, losing out to Nottingham Forest in 1979, and will hope to move one step closer to their first major honour in 41 years.
Of course, with the most successful team in the competition's history first to navigate past, Southampton won't be getting carried away and they will remember having to defend deep and in numbers to earn a goalless draw at home to Liverpool, second in the top-flight, back in November.
That game was the first time since December 2004, also coincidentally against Liverpool, that the Saints failed to register a single shot on target in a Premier League game.
Meanwhile, Klopp's men will hope their trip to the south coast is less like that one and more like their previous League Cup clash, when they thrashed Southampton 6-1 in December 2015, with Divock Origi netting a hat-trick.
Both sides will undoubtedly be keen to put the tie to bed in the first leg, given it would allow them to field a weakened side in the second as they both endure testing fixture schedules, yet that will be no easy task.
Southampton will be without captain and centre-back Jose Fonte after he submitted a transfer request last week, with Puel insisting the 33-year-old could be left out until the end of the January transfer window.
The Portuguese defender turned down a proposed contract extension until 2018, the club's director of football Les Reed has said.
Cedric Soares will return from a head injury sustained in the defeat to Everton earlier this month, while fellow defender Cuco Martina is in contention after illness.
Elsewhere, winger Sofiane Boufal (knee), striker Charlie Austin (shoulder), goalkeeper Alex McCarthy, left-back Matty Targett (both hamstring) and right-back Jeremy Pied (ACL) are all absent. Young midfielder Jake Hesketh is back in training after a knee problem.
Playmaker Philippe Coutinho could return to the Liverpool squad for the first time in seven weeks after recovering from ankle ligament damage, although he isn't match fit enough to start.
Captain Jordan Henderson (heel) and centre-back Joel Matip (ankle) will miss out for the third and seventh successive games respectively, while Loris Karius is likely to start in goal for the second straight game.
Midfielder Marko Grujic is unexpected to be risked after recently returning to training from a tendon issue, although left-back James Milner could return from a calf problem that kept him out of the FA Cup third round draw with Plymouth Argyle on Sunday.
At St Mary's: Southampton - 19 wins, Draws - 12, Liverpool - 12 wins.
At Anfield: Liverpool - 28 wins, Draws - 11, Southampton - 5 wins.
Overall: Southampton - 28 wins, Draws - 24, Liverpool - 51 wins.
Last meeting: Southampton 0-0 Liverpool, Premier League, 19 November 2016.
Last five in all competitions: WLLLD
Last five at home in all competitions: WDWLL
Last five in all competitions: WWWDD
Last five away from home in all competitions: DLWWD
This is the eighth meeting between these two teams in the League Cup, Liverpool having won four of the previous seven - though they have drawn one and lost one of the three clashes at St Mary's.
There were 16 goals scored in the three games between these two sides prior to their 0-0 draw in November.
That goalless stalemate was also the first time the two teams drew at St Mary's since August 2000, nine games before.
Liverpool have won more games in this season's competitions than any other side, with four.
Liverpool have only conceded one goal in four games in the EFL Cup this season, scoring 12.
Southampton are yet to concede a goal in the League Cup in the current campaign. The last time they conceded in this competition was the 6-1 defeat to Liverpool last season.
No Southampton player has yet scored more than a single goal in the EFL Cup, having had five different goalscorers provide their five goals so far.
Daniel Sturridge is the top scorer in this season's competition, with four goals, despite appearing only twice. He has eight goals in six total EFL Cup appearances for Liverpool, with 10 in 12 across his career.
Sturridge scored three goals at St Mary's alone last season and has four goals and two assists in eight appearances against the Saints.
Sturridge's fellow striker Divock Origi also has three goals, with six goals in eight appearances since moving to Merseyside in the summer of 2015.
Premier League regular Neil Swarbrick is the man in the middle for this one, having been appointed frequently for top-flight games since his first in December 2010.
The 51-year-old Lancashire FA official has overseen 21 Premier League games alone this term, including Liverpool's home wins over West Bromwich Albion and Sunderland.
He was also the referee for Southampton's away defeats to Everton and Crystal Palace, as well as a home win over Middlesbrough - all coming inside the past month.
Across his 116 games in the Premier League, Swarbrick has handed out 385 yellow cards but only 13 red cards. The Preston-born referee's most notable duties have seen him act as fourth official in the the 2012-13 Championship play-off final and the 2013-14 League Cup final.