Returning to the ground for the first time since the controversial scenes that plagued the Hammers against Burnley, goals from Joao Mario and Marko Arnautovic earned David Moyes a crucial victory after weeks of growing unease.
There were protests outside of the London Stadium prior to the game, as well as an increased security presence inside the ground, but West Ham fans were fully behind their team throughout a victory that could prove to be a vital turning point for the beleaguered club.
The Hammers took the lead after just 13 minutes when Cheikhou Kouyate broke away at pace to feed Mario, who sent West Ham fans into jubilant celebrations with a powerful finish from the edge of the box.
Mario was involved in the second too, this time as the Portuguese moved down the right to turn a testing ball into the box, which was bundled home by Arnautovic in the 17th minute to give the home side a 2-0 lead.
Arthur Masuaku proved vital on his timely return to the side from suspension and the full-back produced a crucial cross for Arnautovic during first-half stoppage time, allowing the Austrian to pull off a wonderful volley to give the Hammers a three-goal cushion at the break.
Southampton appeared off the pace throughout proceedings, but they might just have grabbed a goal back when Dusan Tadic provided some quality out on the flanks, only for Nathan Redmond to head wide of Joe Hart's goal.
Arnautovic was arguably West Ham's greatest threat and he could have bagged himself a hat-trick before being substituted, but the playmaker saw his driven shot kept out of the bottom corner by a diving Alex McCarthy.
Victory for Moyes and his men has lifted the Hammers away from the relegation zone and they now sit on 33 points in 14th place in the league standings.
As for Mark Hughes and his charges, the coastal club find themselves in real danger of facing the drop, with Saints sitting in 18th place and two points adrift of currently-safe Crystal Palace.
What will inspire Hughes, though, is that Southampton do have a game in hand over both the Eagles and Huddersfield Town, meaning that a victory in that contest could lift them away from the bottom three in the weeks to come.
WEST HAM UNITED (3-4-3): Hart; Rice, Ogbonna, Cresswell; Zabaleta, Kouyate (Cullen 89'), Noble, Masuaku; Antonio (Fernandes 9'), Joao Mario, Arnautovic (Hugill 80')
SOUTHAMPTON (4-4-2): McCarthy; Soares, Stephens, Hoedt, Bertrand; Tadic, Lemina, Hojbjerg, Redmond (Boufal 67'); Austin (Carrillo 83'), Gabbiadini (Long 46')