With the Championship outfits playing out a 1-1 draw in the initial tie, they went to a replay at St Mary’s on Tuesday night.
That resulted in a 3-0 win for Southampton, who will now head to Anfield for an 8pm kickoff (GMT) on Wednesday, February 28.
It will be the first time Liverpool have faced Southampton since a strange 4-4 at St Mary’s on the final day of the Premier League last season, and will be their 20th meeting of Jurgen Klopp‘s tenure.
Southampton are now managed by Russell Martin, who was appointed in June following impressive spells in charge of MK Dons and Swansea.
Martin’s side are currently second in the Championship, 11 points off leaders Leicester, with Adam Armstrong their top scorer for the season so far.
Kyle Walker-Peters, Gavin Bazunu, Jan Bednarek and Stuart Armstrong are among the most familiar names in Martin’s squad, and are all important players.
The Reds have had six different goalscorers in this season’s competition, with Diogo Jota, Curtis Jones, Ryan Gravenberch, Luis Diaz, Darwin Nunez and Virgil van Dijk all finding the back of the net once.