The Hammers will be desperately looking to get the fans back on their side in their first home game since the 3-0 defeat to Burnley earlier this month. The loss was heavily marred by a number of pitch invasions, vehement protests against the club's board and general fan unrest.
The Saints, who despite recently progressing to the FA Cup semi finals stage have won only once in their last five league games, currently sit in 18th place. With their opponents only two points above them in 17th, a win will be the only acceptable result in this bottom of the table clash.
Here's everything you need to know ahead of the game at the London Stadium:
Things were looking a lot better for West Ham back in February 2014. Under former manager Sam Allardyce, they earned their fourth consecutive league victory with a 3-1 win over the Saints.
After Maya Yoshida's early goal put Southampton ahead in the 8th minute, the Hammers produced a spirited comeback to go into half-time 2-1 up, courtesy of two goals in three minutes from Matthew Jarvis and Carlton Cole.
Then, in the second half, Kevin Nolan scored a close range volley to secure the three points and give him his fifth goal of the month. The win sent the Hammers up to a comfortable 10th place, well out of sight of the relegation zone.
How times have changed!
Marko Arnautović vs Charlie Austin
Marko Arnautović produced some fine form over the international break. In action for Austria, he scored two against Slovenia before netting another against Luxembourg, and will be full of confidence coming into this fixture.
Likewise, if Southampton's Charlie Austin is to start, which Mark Hughes has suggested, he could be another to watch in this game. Coming back from injury, he will be determined to get his name on the scoresheet.
Austin netted the stoppage-time winner for the Saints in August's reverse fixture, so he is definitely one to look out for.
West Ham's Manuel Lanzini scored his first goal for Argentina during the international break, but later missed training for the Spain game due to a knock that he'd picked up. Lanzini still remains a doubt, alongside James Collins, who will have his hamstring injury assessed before any further judgement on his participation is made.
Edimilson Fernandes looks to have recovered from his ankle injury and could be welcomed back into the starting lineup this weekend. However, four key players in Andy Carroll, Winston Reid, Sam Byram and Pedro Obiang will remain on the sidelines.
For Southampton, Steven Davis is likely to be kept out of action with a hamstring problem. However, Charlie Austin has recovered from a thigh injury and could make a start for the first time since late December.
Ryan Bertrand, although withdrawn from the England squad as a precaution, could come back for Mark Hughes' first Southampton league XI as boss.
Potential West Ham Starting Lineup: Adrian; Collins, Ogbonna, Cresswell; Zabaleta, Kouyate, Noble, Antonio; Joao, Arnautović, Lanzini.
Potential Southampton Starting Lineup: McCarthy; Cedric, Stephens, Hoedt, Bertrand; Hojblerg, Lemina; Ward-Prowse, Tadic, Redmond; Austin.
With West Ham on a very poor run of form, having conceded 11 goals in their last three league games, this is a must-win game for them.
However, with the toxic atmosphere around the east London club at the moment, it will be a real struggle in front of the home crowd. If the Hammers concede a goal first, the fans will definitely let them know about it, and players' heads could start to fall again.
Being Mark Hughes' first league game, off the back of that recent FA Cup win at Wigan, the Saints will be full of energy and fight, ready to impress the new gaffer. That newfound optimism could be the difference in this all-important clash.
Having said that, Hughes hasn’t won his first Premier League match in charge of a club since September 2004 at Blackburn. So, perhaps the odds might be in West Ham's favour this time.
Whatever happens, it is likely to be a very exciting affair, with neither team wishing for a draw.
Prediction: West Ham 1-2 Southampton