It’s the first meeting between the fierce south-coast rivals since the 2011-12 season, when both games finished in draws.
Here’s all you need to know ahead of the highly-anticipated game at Fratton Park...
Pompey team news
Denver Hume: Portsmouth's expensive forgotten man and why former Sunderland defender really could be one for the future
'We wanted to show him a bit of love' - Portsmouth-based Spurs fans' terrific gesture to ensure Dane Scarlett feels at home on the south-coast
League One latest: Portsmouth linked duo set for Oxford United and Lincoln moves, Southampton prospect joins Blues rivals as Ipswich land former Blackpool and Derby veteran
'Real driving force... lion-hearted display... classy presence' - Neil Allen's Portsmouth ratings from 3-0 Carabao Cup win at Cardiff
'We’ve got a real problem': Portsmouth boss reveals headache after career first at Cardiff
Oli Hawkins looks set to continue in central defence against Southampton.
The striker was again converted back to a defender for Saturday’s 1-0 loss at Wycombe.
Nevertheless, Hawkins delivered a man-of-the-match performance alongside Christian Burgess and Kenny Jackett’s likely to retain that centre-back pairing for the south-coast derby.
Captain Tom Naylor is a doubt after sustaining two knocks at Adams Park.
If he's not fit then Ross McCrorie will come into the starting line-up.
Ellis Harrison is suspended following his dismissal against the Chairboys, which may mean Gareth Evans features on the right-wing.
Third-year scholar Leon Maloney will be on the substitutes’ bench.
Craig MacGillivray; James Bolton, Christian Burgess, Oli Hawkins, Brandon Haunstrup; Ross McCrorie, Ben Close; Gareth Evans, Andy Cannon, Ronan Curtis; John Marquis.
Subs: Alex Bass, Sean Raggett, Paul Downing, Anton Walkes, Ryan Williams, Leon Maloney, Brett Pitman.
Southampton team news
Southampton boss Ralph Hasenhuttl has admitted he’ll field his strongest side possible for the trip to Fratton Park.
However, that will not include winger Moussa Djenepo – Saints’ £15m summer signing from Standard Liege.
The Mali international has scored twice for the St Mary’s outfit this season and is their current top scorer.
Yet he sat out Southampton’s 3-1 defeat against Bournemouth with a muscle issue and will not be fit to face the Blues.
Nathan Redmond is an injury doubt after returning to the Saints starting XI against the Cherries following an ankle problem.
The England wide man suffered cramp on his return and may not be risked.
Angus Gunn; Kevin Danso, Jan Bednarek, Jannik Vestergaard, Cédric Soares; Oriol Romeu, Pierre-Emile Højbjerg, James Ward-Prowse, Sofiane Boufal; Che Adams, Danny Ings.
Subs: Alex McCarthy, Maya Yoshida, Yan Valery, Jack Stephens, Stuart Armstrong, Shane Long, Ryan Bertrand.
1-0 11/1; 2-0 20/1; 2-1 11/1; 3-0 55/1; 3-1 33/1; 3-2 33/1
1-0 13/2; 2-0 8/1; 2-1 7/1; 3-0 14/1; 3-1 12/1; 3-2 22/1
0-0 10/1; 1-1 11/2; 2-2 12/1; 3-3 50/1
Kevin Friend (Leicestershire)
Tonight (7.45pm kick offs unless stated)
Arsenal v Nottingham Forest, Colchester United v Tottenham, Crawley Town v Stoke City, Luton Town v Leicester City, Preston North End v Manchester City, Sheffield Wednesday v Everton, Watford v Swansea City.
Tomorrow (7.45pm kick offs unless stated)
Brighton v Aston Villa, Burton Albion v AFC Bournemouth, Chelsea v Grimsby Town, Manchester United v Rochdale, MK Dons v Liverpool, Oxford United v West Ham United, Sheffield United v Sunderland, Wolves v Reading.
Head to head
P11 W5 D3 L3
Top scorer: Ellis Harrison (4)
Most assists: John Marquis, Ronan Curtis, Brandon Haunstrup (all 2)
Most games: Tom Naylor (10)
P7 W3 D1 L3
Top scorer: Moussa Djenepo (2)
Most assists: Sofiane Boufal (2)
Most games: Jan Bednarek, Oriol Romeu, James Ward-Prowse, Pierre-Emile Højbjerg, Danny Ings (all 7)
L 1-0 Wycombe (A) League One
D 2-2 Burton Albion (H) League One
W 3-1 Norwich under-21s (H) EFL Trophy
W 1-0 Crawley (H) EFL Trophy
D 1-1 Blackpool (A) League One
L 3-1 Bournemouth (H) Premier League
W 1-0 Sheffield United (A) Premier League
D 1-1 Manchester United (H) Premier League
W 1-0 Fulham (A) Carabao Cup
W 2-0 Brighton (A) Premier League