The visitors will be full of confidence given their recent run and the fact that they thumped the Gunners in the reverse just over a month ago on Boxing Day.
Things have not been going the Gunners' way of late in the Premier League, but they put that behind them on Saturday by winning in the FA Cup for the 14th match in a row.
Arsene Wenger's side have won the competition the last two years and a record 12 times overall, and they will be even more confident of making it three on the bounce after a favourable fifth-round draw.
With all the so-called big boys in the pot, Arsenal were drawn at home against Championship side Hull City. It is the third season in a row that the Tigers and Gunners will meet, with Arsenal winning 3-2 in extra time in the 2014 final before seeing them off 2-0 in last year's third round.
After making his return off the bench in the 1-0 defeat to Chelsea on January 24, Alexis Sanchez made his first start since November on Saturday and scored the winner after Burnley equalised through Sam Vokes.
The Chilean, who coincidentally has scored in both of his appearances against Southampton at the Emirates, has been his usual buzzy self in his first two appearances of the New Year and his return might spark a return to form for the North London side, who are without a win in three league games.
That dip in form has seen Wenger's side drop to third in the table, behind Manchester City on goal difference and three adrift of surprise leaders Leicester City, who will simply not go away.
The recent defeat to Chelsea, in which Per Mertesacker was sent off for a professional foul, ended a nine-match unbeaten run at home in the league since the opening-day defeat to West Ham.
Recent Premier League form: LWWDDL
Recent form (all competitions): WWDDLW
The Saints were not in action over the weekend after losing at home to Crystal Palace in the FA Cup third round, so tomorrow it will have been nine days since their last match, and what a result it was too.
Ronald Koeman's side went to Old Trafford and frustrated Manchester United for the majority before snatching a late winner through Charlie Austin, who came off the bench and powered home a header for the most memorable of debuts.
That goal means that Southampton have scored a league-high 10 headed goals so far in 2015-16 and they have also fired in the most crosses from open play this term - it should be a recipe for success with Austin wasting no time to break his duck.
Victory at Old Trafford made it three wins and three clean sheets in a row for the Saints, who are up to eighth and just four points behind Man Utd in fifth.
Austin has been the club's only new arrival in January and it looks set to remain that way on deadline day today. Victor Wanyama and Sadio Mane have both been heavily linked with moves away both this month and last summer, but it seems that they will be staying at St Mary's at least until the end of the season.
The Saints' return to form and new-found defensive stability has, perhaps unsurprisingly, coincided with the return of Fraser Forster after 10 months out. The goalkeeper has had no problem finding his feet and both he and Jack Butland look set to push Joe Hart all the way for England's No.1 jersey at Euro 2016.
Recent Premier League form: WLLWWW
Recent form (all competitions): LLLWWW
Wenger said at his press conference this morning that everyone who featured against Burnley was available apart from Tomas Rosicky, who is expected to be out for another month after coming off the bench for his first appearance of the season but then suffering a fresh thigh injury.
Mertesacker will return in defence after serving a one-match ban for his red card against Chelsea, while elsewhere the likes of Petr Cech, Hector Bellerin, Aaron Ramsey and Mesut Ozil should also be back.
Mohamed Elneny and Francis Coquelin played together in midfield for the first time against the Clarets and Elneny looked especially bright on his Gunners debut, but it would be a surprise to see him keep his place here.
The big question for the visitors is whether Austin will make his first start after netting the winner off the bench at Old Trafford.
Graziano Pelle is struggling with a knee injury and has not been starting of late, so it will be up to Koeman whether to promote Austin, who has scored in each of his two Premier League appearances against Arsenal, to the first team or stick with Shane Long in attack.
Arsenal possible starting lineup:
Cech; Bellerin, Mertesacker, Koscielny, Monreal; Coquelin, Ramsey; Walcott, Ozil, Sanchez; Giroud
Southampton possible starting lineup:
Forster; Cedric, Van Dijk, Fonte, Bertrand; Wanyama, Clasie; Tadic, Mane, Targett; Austin
Head To Head
It was a memorable night at St Mary's on Boxing Day when the Saints put four past Wenger's side. It means that the South Coast club have won three and lost just one of the last five matches against the Gunners in all competitions.
Wenger has come up against Koeman on 10 occasions as Arsenal manager, winning just two of those matches (D4 L4).
We say: Arsenal 2-1 Southampton
With Southampton in such fine form of late, it is possible that they could do the double over the Gunners, especially as they were not in action at the weekend. Still, the return of Sanchez should not be underestimated and he could help fire the hosts to a narrow victory.