Mauricio Pochettino's side had won six successive matches in all competitions before being beaten 4-2 by fierce rivals Arsenal in Sunday's north London derby.
Southampton have failed to win any of their last eight matches and, after squandering a two-goal lead against Manchester United at St Mary's on Saturday evening, the club's hierarchy called time on Mark Hughes' reign as manager on Monday morning.
Spurs are 7/20 (1.35) favourites with William Hill to make an immediate return to winning ways on Wednesday.
Kelvin Davis will be the main man in the away dugout on Wednesday and William Hill offer 8/1 (9.0) that the caretaker boss steers his side to victory, while the same firm go 4/1 (5.0) that the Saints secure their fifth draw in seven league matches.
Jan Vertonghen was sent off in the closing stages against Arsenal, while Erik Lamela faces a race to be fit. Victor Wanyama, Mousa Dembele and Davinson Sanchez are out and this match is likely to come too soon for Kieran Trippier.
Southampton will hope that Ryan Bertrand is fit enough to play, but strikers Danny Ings and Shane Long are likely to miss out again for the visitors.
Goals at both ends?
Spurs have kept just one clean sheet in five Premier League matches at Wembley so far this season, while Southampton have scored six goals in their last four fixtures in this competition.
Spurs have scored more than one goal in the first half of three of their last four Premier League matches, while Southampton have shipped eight first half goals in their last four league matches.
As such, the juicy 5/2 (3.50) quote for Pochettino's team to score more than once before the break could represent real value for punters ahead of Wednesday's clash.