Chelsea at home await the winners of this fourth round tie at a stage in the competition that Saints have not reached since the 2003/04 season when they were beaten by eventual finalists, Bolton Wanderers.
Victories over Championship side Barnsley, and League One outfit Bristol City, have put Southampton into the last 16, and this game provides the team with a chance to make it nine games without defeat in all competitions as their recent good form continues to gather pace.
The two teams met at St Mary’s earlier in the season where a 1-1 draw was played out. Jose Fonte’s late header earned a point for the hosts on that day.
Since then, Sunderland have endured a rollercoaster of emotions both on and off the pitch, led by the dismissal of Paolo Di Canio as the club’s manager. Di Canio has been replaced by Gus Poyet, a man whose duels with Saints in the lower leagues with Brighton provided plenty of entertainment.
Poyet faces a tough challenge at the Stadium of Light with the Black Cats having picked up just four points from their opening ten league games, so he will surely use this cup tie as a chance not only to break away from that pressure, but also to assess his squad.
The likes of Phil Bardsley and Lee Catermole are back in favour, though the latter’s red card at Hull on Saturday may jeopardise the midfielder’s place in the team on Wednesday.
On the connections side of current players, only Kelvin Davis has featured for both teams during his career. Davis was part of a Sunderland side that endured a difficult Premier League season in 2005/06, but in his own words: “a lot of water has gone under the bridge since then.”
Mauricio Pochettino will decide whether to pursue with the approach which has served him well in this competition so far. This would see players with limited playing time in the league so far this season, earn a run out on Wearside.
On Saturday, Steven Davis returned from the knock that kept him out of the Fulham game, but was only named amongst the substitutes at Stoke. Guly do Prado remains out with a knee injury.
Sunderland are likely to give defender Wes Brown a full run out as the 34 year-old steps up his return from injury. The former Manchester United man was a second half substitute in Saturday’s 1-0 defeat to Hull City in the Barclays Premier League.
That defeat to the Tigers came at further cost, with goalkeeper Kieren Westwood leaving the pitch before half-time with an injury, whilst both Andrea Dossena and Lee Cattermole were sent off in an eventful game at the KC Stadium.
The two teams have already met in the Premier League this season, playing out a 1-1 draw in the opening game at St Mary’s
Jose Fonte’s 88th minute header earned the home side a point after falling behind to Emanuele Giaccherini’s first half opener.
Sunderland got the better of Saints in this fixture last season, running out 1-0 victors when they came to St Mary's last December thanks to Fletcher's goal just before the break.
The two sides shared the spoils at the Stadium of Light in the final away game of the 2012/13 campaign, and are due to meet again up there after this tie on Saturday 18th January, kick-off 12:45pm.
It is more than a decade since Southampton last beat Sunderland, having done the double over the Black Cats in the 2002/03 season.
Overall, the two sides have met 58 times in competitive matches. 23 of those have gone Saints' way, 21 have ended in Sunderland wins and 14 have ended up with honours even.
Lee Mason will referee Wednesday’s game, and he will be assisted by Mr D England and Mr S Ledger. Craig Pawson is the fourth official.
As with every First Team game, we'll be providing minute-by-minute coverage throughout the day on our official Twitter feed
plus goal updates on our official Facebook page
You can listen to live commentary courtesy of BBC Solent on Saints Player
, where you can keep up to date with all the stats and scores from around the country.
Kelvin Davis spoke to Saints Player ahead of the game, and you can watch his interview in full now.