Mauricio Pochettino will face his former club for the sixth time since leaving St Mary's for Spurs in May 2014 - recording three wins, one draw and one defeat, with the loss coming in last season's clash at the Lane.
Spurs are expected to start with Son Heung-min up front after the news this week that top-scorer Harry Kane is facing around a month on the sidelines with an ankle injury.
Mousa Dembele has been passed fit to take his place in the matchday squad, but Kyle Walker and Victor Wanyama are doubtful and could undergo late fitness tests.
As for Southampton, they have moved into the top half and have games in hand on a number of their rivals after their run to the final of the League Cup.
Manolo Gabbiadini has been their main man after joining from Napoli in January, scoring six goals in four matches for Saints.
Claude Puel has no fresh injury worries and is expected to name an unchanged side from that beat Watford last time out, on March 4. Charlie Austin is said to be making good progress from a shoulder problem, but Sunday's game will come too soon for the striker.