The south coast side lost 6-1 on their last visit to the Emirates but, now boasting the meanest defence in the league, they will pose a sterner test for the Gunners
Mauricio Pochettino's men have lost just one match so far this season - a record matched only by Everton - and are looking to extend their unbeaten run to nine.
Victory by more than one goal would see Southampton climb above their opponents and potentially to the top of the league, depending on the result of the Merseyside derby earlier in the day.
Arsenal will want to bounce back from a 1-0 defeat to Manchester United last time out. That result brought an end to a run of nine matches without defeat and reduced the Gunners' lead at the top to two points over second-placed Liverpool.
However, last season's meeting at the Emirates will not be far from the minds of Southampton players and fans alike, with the men from the south coast having fallen to a 6-1 defeat.
Jos Hooiveld and Nathaniel Clyne netted own goals in that encounter, with a strike by former Southampton winger Theo Walcott rubbing salt in the wound two minutes from time.
Despite Arsenal's success that day, three of the last four matches between the sides have ended all-square, including the most recent - a 1-1 draw at St Mary's Stadium in January.
Southampton manager Pochettino is well aware of the threat posed by Arsenal midfield maestro Mesut Ozil.
"Way back when he was playing in Germany he was already showing signs of brilliance with his skills," said Pochettino.
"At Real Madrid he acquired a lot more experience at European level and as a general player he added to his game. As a player I rate him as one of the top 10 players right now on the European stage."
Walcott (abdominal injury) has reportedly been cleared to return against his former club, while Aaron Ramsey is likely to play after missing Wales' friendly against Finland, with coach Chris Coleman claiming the midfielder felt under the weather.
Alex Oxlade-Chamberlain (knee) will not feature, but Lukas Podolski is nearing a first-team return (hamstring).
Southampton will be without Jack Cork (ankle) and long-term absentee Guly do Prado (knee).