Spurs were dumped out of the Carabao Cup by League Two minnows Colchester and are 33 points behind Premier League leaders Liverpool.
Meanwhile, they face a tricky-looking Champions League last-16 clash with Bundesliga leaders RB Leipzig next month.
Tottenham's FA Cup fourth round tie against Southampton is by no means an easy game for Jose Mourinho’s men.
The Saints have won six of their last eight games in all competitions and have climbed to ninth in the table.
Ralph Hasenhuttl's side are just three points behind Tottenham, who needed a third round replay to get past Championship club Middlesbrough.
Mourinho is expected to name a strong starting XI after his players suffered a shock 1-0 defeat at St Mary's on New Year's Day.
Paulo Gazzaniga is likely to come back in for Hugo Lloris, who returned in Wednesday's 2-1 win over Norwich after recovering from a dislocated elbow, which sidelined him for three months.
Japhet Tanganga, who has impressed in recent games against Liverpool, Middlesbrough and Watford, could come in for Serge Aurier.
Meanwhile, Ryan Sessegnon is Tottenham's only available left-back with Ben Davies injured and Danny Rose reportedly edging closer to the exit door.
Davison Sanchez and Jan Vertonghen could start in the middle of defence, with Toby Alderweireld rested.
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Club-record signing Tanguy Ndombele is expected to partner Eric Dier in midfield after Harry Winks was forced off with an ankle injury against Norwich.
Meanwhile, an attacking trio of Erik Lamela, Christian Eriksen and Gedson Fernandes could feature behind Heung Min Son.
Tottenham look set to have a strong bench with Dele Alli, Giovani Lo Celso and young striker Troy Parrott watching on.
The FA Cup is Tottenham's most realistic chance of winning silverware this season.