It's a repeat of the fixture just 24 days before this one, and the Blues will hope the game is in a similar fashion, as they ran out 3-1 winners last time.
Ralph Hassenhuttl's side haven't had the greatest start to the season, with the Saints currently languishing in 16th place in the Premier League, having only amassed eight points.
With only one league win this season, and being forced into a penalty shootout against Sheffield United in the previous round of the cup, it's pretty clear who the underdogs will be in this one.
As for Chelsea, there's not been much that can be complained about whatsoever thus far, with the West London side leading the way in the league, having only conceded three goals.
They too made hard work of their third round win in the cup however, requiring penalties to get past Aston Villa, but it's hard to see how they could be anything but favourites against their upcoming opponents.
Prior to the game, Thomas Tuchel spoke to the press and said: 'The game was too early [for N'Golo Kante]. If the match would have been on Sunday he would have played. So he is fully available for Tuesday and for Newcastle.'
The return of N'Golo Kante is a positive one, with the Frenchman always an excellent player to have at a manager's disposal, even if he is unlikely to play in a fixture considered by many to be of less importance.
Ralph Hassenhuttl also had a pre-match press conference and told the media: '[Mohamed Elyounoussi] will have his operation on Monday. He will miss the Chelsea game, but this is normal. He needs to have two or three days' rest before he can train again.'
Also absent will be striker Armando Broja who is unavailable due to the fact he is on loan from Chelsea and therefore is not eligibile to face his parent club.
Kepa; Christensen, Chalobah, Sarr; James, Loftus-Cheek, Saul, Alonso; Barkley, Havertz, Ziyech
Forster; Valery, Lyanco, Salisu, Perraud; Tella, Diallo, Romeu, Djenepo; Adams, A. Armstrong
As mentioned earlier, Chelsea fans will be absolutely delighted with the first few months of this season, riding high in the Premier League and looking strong in other competitions too.
The Kova pass. 🤤— Chelsea FC (@ChelseaFC) October 24, 2021
The silky Cal finish. 😍 pic.twitter.com/BYjVAqLH8z
They've faced some strong sides already, including multiple London derbies, but have come through most relatively unscathed and will want to push on in this competition for the first silverware of the season.
On the other hand, it's not been the most inspiring start for the South Coast-based club, who are currently just two places above the relegation zone with only a single win to their name in the league.
Tino's box of tricks ✨ pic.twitter.com/ojr228DEFQ— Southampton FC (@SouthamptonFC) October 24, 2021
Ones To Watch
That said, with the German expected to start once again, he could be one to look out for, especially as it feels as though he needs a goal to get his season back on track.
The striker has started all but two Premier League games this season but has so far failed to make a material impact, only scoring a single goal, that coming on his debut on the opening day.
Since then he has done very little, but a change in competition may inspire him to regain the goalscoring form he had at his previous club, where he notched up 58 goals in 151 appearances.
Previous Five Meetings
These two clubs have played one another a total of 109 times over the course of history, with the Blues coming out on top on 47 occasions, the Saints 31 times and it being a stalemate after 31 games too.
With regards to the previous five meetings however, it has been a little closer than that record might suggest, going back to October 2019 for the fifth most recent fixture.
That one ended in a Chelsea win, and convincingly so as well, with then Frank Lampard's side defeating their opponents 4-1 at St Mary's Stadium, courtesy of goals from Mason Mount and Tammy Abraham, among others.
During the 2020/21 season, it was a tale of two draws, both at home and away - though each one was under a different manager for the Stamford Bridge-based side.
The first came in October 2020, when the sides played out an entertaining 3-3 draw that ended with a last minute Jannik Vestergaard equaliser for the visitors that day.
A second draw followed a few months afterwards, though with Thomas Tuchel now at the helm, but it was a similar pattern to that of his predecessor's performance in the same game.
Takumi Minamino's first half opener was cancelled out by a Mason Mount penalty, but neither side could go on to claim the win, and they both went away disappointed not to have got more from the game.
Finally, in the most recent matchup between the sides, Chelsea secured a 3-1 win at home to the Saints just a few weeks ago, although the scoreline doesn't necessarily reflect the game.
'I thought it hit the post so I just played on!' 😅— Chelsea FC (@ChelseaFC) October 4, 2021
VAR checks, red cards and two goals in the last ten minutes all came together in combination to eventually give the home side all three points, much to the relief of many watching at home and indeed in the stadium.
How To Watch
Viewers in the UK will be unable to watch this game live but it can be followed on the TV via Sky Sports News who will be giving regular updates from the game.
Otherwise, you can also follow the game right here on VAVEL where there will be live updates throughout the game.