Things are going from bad to worse for the Hammers at the moment and defeat will be an even more bitter given that Charlie Austin - a man who the Hammers opted not to sign due to fitness concerns - gave Southampton the lead.
In an uneventful first half, Austin fired past Adrian in the West Ham goal after Ryan Bertrand pulled back for the former QPR striker.
West Ham tried to change things by bringing on Sofiane Feghouli for Mauel Lanzini at half-time, but the Saints were easily the superior side in the second 45 minutes.
Just after the hour mark, Austin was involved once again as Southampton as he assisted Dusan Tadic for Southampton's second goal.
Southampton weren't finished there, and James Ward-Prowse topped off an impressive afternoon for the Saints when he converted Steve Davis' cut-back in added time.
The Hammers have now conceded 11 goals in their last three games, and if this wasn't bad enough, the man with 'no ligaments in his knee' was central in another defeat at the London Stadium.