The Gunners slipped to fifth in the Premier League in their last outing, and they'll be hoping to climb back into the top four with a win at St Mary's Stadium.
Read on for a closer look at the clash, but first, here are the viewing details:
Date: Sunday, December 10
Time: 12 p.m. GMT/7 a.m. ET
TV: BT Sport 1 (UK), NBCSN (USA)
Aside from long-term absentee Santi Cazorla, Shkodran Mustafi is the only fitness concern for Arsenal ahead of the match, though he may still feature.
According to The Sun's Gary Stonehouse, Arsenal boss Arsene Wenger said ahead of the Gunners' clash with BATE Borisov on Thursday: "Everybody is available. There is a small problem with Mustafi from Saturday but everybody else looks alright. He’s got a little thigh problem, but it’s a small one. He could be available for Southampton."
Meanwhile, according to Transfermarkt, Southampton are injury-free for the clash.
Arsenal were left wondering how they failed to get even a point against United in the last round of fixtures after they bombarded the Red Devils with 33 shots.
It was a thrilling end-to-end contest that the Gunners largely dominated after finding themselves 2-0 down inside 12 minutes thanks to two glaring errors at the back and some ruthless finishing from their opponents.
However, they only managed to beat David De Gea once as the Spaniard produced a stunning performance, leaving Arsenal to rue their early mistakes.
ESPN FC's Mattias Karen believed the Gunners set themselves too big a task:
Had De Gea not played so well and had they been awarded a penalty for Matteo Darmian's foul on Danny Welbeck, they could well have completed a comeback and won the match.
Bleacher Report's James McNicholas was entertained despite the defeat:
If the Gunners can replicate that attacking performance against Southampton—or virtually any side in the Premier League—they'll almost certainly come away with three points barring an exceptional goalkeeping performance reminiscent of De Gea's.
However, they cannot afford to gift opponents the chance to score, even if they're not as clinical as United, so they need to cut out such carelessness at the back.
Southampton have played fairly well of late, having beaten Everton 4-1 and drawn 1-1 at Bournemouth either side of a defeat to Manchester City. Such was their performance against the Premier League leaders, they were only denied a point by a last-gasp Raheem Sterling winner.
If they can put together a similar showing by remaining organised and disciplined at the back and carrying a threat going forward, they'll give themselves a good chance of getting something out of the game, but much will depend on the quality of Arsenal's play at either end.