Here, we take a walk down memory lane and look back at who history favours this weekend at Wembley, and remember some of the classic encounters which have occurred since the maiden meeting in 1897.
As you'd expect for a team so dominant in English football over the years, the head-to-head honours favour Manchester United.
The Red Devils have won 62 and drawn 30 of the previous 119 fixtures, while Southampton trail behind with 27 successes to their name over the 120-year period.
United have enjoyed lengthy unbeaten runs against their opponents over the years, including an 11-match undefeated streak that stretched 11 years between 2004 and 2015.
Over 90 minutes, they also put together an 18-game sequence between 1989 and 1996, but the Saints did knock Sir Alex Ferguson's side out of the FA Cup on penalties during that period.
EFL Cup Final 2017: Click here for key information ahead of this year's FinalDell delight for dominant United
Southampton 1-3 Manchester United
Saturday 22nd April 2000
Manchester United's 1999/00 Premier League campaign was a record-breaking one, marching to their sixth title in eight years by an unprecedented 18-point margin.
The crown was clinched at The Dell, with a trademark David Beckham free-kick being followed up by a Francis Benali own goal and an Ole Gunnar Solskjaer effort.
Southampton's sole success
Manchester United 0-1 Southampton
Saturday 1st May 1976
FA Cup Final
The most famous day in Southampton's history saw the club topple Manchester United at Wembley Stadium, with Bob Stokes' late goal securing their one and only major trophy to date.
Stokes broke the deadlock in the 83rd minute, firing beyond Alex Stepney to write himself into Saints folklore.
The best of the rest
Southampton 3-1 Manchester United
Saturday 13th April 1996
The game that will not be remembered so much for the result, but more for Sir Alex Ferguson's reasoning behind his side's first-half horror show.
Trailing 3-0 at the break, the Scot believed his players were having trouble seeing each other in their grey away kit, and sent them back out in a blue and white strip. United grabbed a late consolation to reduce the arrears.
Southampton 6-3 Manchester United
Saturday 26th October 1996
One of the most memorable results of the Premier League era, Southampton were one goal to the good through Eyal Berkovic before Roy Keane was dismissed with 21 minutes played.
Another Berkovic strike, a deft Matt le Tissier chip, an Egil Ostenstad brace and an own goal helped the Saints to an emphatic win at The Dell.
Manchester United 6-1 Southampton
Saturday 22nd December 2001
Five years on from being hit for six in that aforementioned loss, Manchester United finally returned the favour with a thumping win just before Christmas.
Ruud van Nistelrooy struck after 31 seconds on his way to an emphatic hat-trick, with Solksjaer, Keane and Phil Neville getting in on the act.