The 3-0 defeat to Chelsea on Monday night leaves the Baggies seven points off safety with 11 league games to go. And what made the loss even more difficult to take was the injury sustained by Daniel Sturridge just four minutes into the game at Stamford Bridge.
Even if he was fit for the game against the Saints, it seems highly unlikely that he would be risked for the tie anyway, so perhaps the most likely strike-force that Alan Pardew will pick will be Salomon Rondon and Jay Rodriguez.
There are likely to be a number of changes across the pitch for West Brom, including rare starts for both Sam Field and Oliver Burke in midfield. Burke has struggled since his £15 million move, so a cup game may be a great chance for the winger to play with some freedom.
There is also a start for James McClean on the other wing in the predicted lineup. He has been a more peripheral figure this term, so he will be hoping to impress against Mauricio Pellegrino's side.
Alongside Ahmed Hegazi in the back four is Allan Nyom, Gareth McAuley and Chris Brunt. And they will be looking to improve from the last time Southampton visited The Hawthorns when the Saints scored three times to bag a vital three points near the bottom of the table.
With that in mind, here is a look at the predicted lineup in full...