Arsene Wenger's side can pile the pressure on Manchester City and Chelsea with a victory against a Saints side which has dealt well with the departure of chairman Nicola Cortese.
Arsene Wenger's side has found remarkable consistency since the 6-3 loss at title rivals Manchester City in December, claiming seven consecutive triumphs in all competitions.
That run has left the London club fighting for silverware on three fronts, and has also silenced the doubters who suggested that Arsenal's Etihad mauling would spell the end of its championship challenge.
Wenger's charges have not lost to Southampton since November 2002 but can expect a stern test at St Mary's as they attempt to stretch their lead at the top of the table, with City and Chelsea not in action until Wednesday.
Alex Oxlade-Chamberlain made his first Arsenal start since August against Coventry following a long injury break.
The forward could be back on the substitutes' bench against his former club, but he is relishing the prospect of returning to the south coast once again.
"To go back there in any sense is always really nice, especially when we go to play them,' he told Arsenal's official website. "Last season I went back there and it was a surreal feeling for me, warming up on the opposite side of the pitch and being in the opposite dressing room.
"It was the first time I went back there to play, so it was a bit weird for me. I'm looking forward to going back this season, obviously they're doing really well so it's a tough game for us."
Lukas Podolski staked his claim for a starting berth by scoring twice against Coventry, but the Germany international could also return to the bench.
Mikel Arteta (calf), Aaron Ramsey (thigh), Tomas Rosicky (broken nose) and Thomas Vermaelen (knee) are set to be back in contention.
The likes of Wojciech Szczesny, Santi Cazorla, Olivier Giroud and Bacary Sagna are expected to be restored to the starting lineup.
Abou Diaby and Theo Walcott (both knee) are long-term absentees.
Southampton has won its last three home games and striker Guly do Prado warned Arsenal not to expect an easy ride after scoring in Saturday's FA Cup win over Yeovil Town.
"We get confidence from these wins," the striker told the club's official website. "We play for a win in every game, whether it’s in the FA Cup or the Premier League.
"The win today will give us confidence for Tuesday night against Arsenal. Now we have to think about that because it's going to be another big, hard game – but we are going to play to win."
Rickie Lambert (hamstring) and Artur Boruc (back) are expected to return after missing the clash with Yeovil and Victor Wanyama (calf) could feature for the first time since early last month.
Pablo Daniel Osvaldo is still suspended following a training ground incident, while Dejan Lovren and Gaston Ramirez (both ankle) remain sidelined.