The Saints are just two points above the drop zone heading into this weekend's fixtures.
With Cardiff chasing them, Southampton know they cannot afford to slip up on the south coast.
Southampton have won just one of their last six matches and they will be without star striker Danny Ings this weekend.
Ings is struggling with a hamstring problem and the Saints coaching staff have decided to wait for their following game in three weeks time.
Midfielder Mario Lemina is nearing a return after abdominal surgery.
Tottenham head into the game in good spirits after beating Borussia Dortmund in midweek in the Champions League.
Coach Mauricio Pochettino could include Dele Alli for the first time since suffering a hamstring strain seven weeks ago.
Harry Winks is a doubt with a recurring groin problem, while Eric Dier returned from tonsillitis to play on Tuesday night.
Ralph Hassenhuttl's troops have not won any of their last six home league games against Spurs since returning to the Premier League in 2012.
Following a three-match winless run in the Premier League, Tottenham will be looking to return to winning ways when they travel to St. Mary’s.
After facing successive defeats to Burnley and Chelsea, Spurs then went on to draw against Arsenal at Wembley. This three-match run has all but ended Tottenham’s title challenge and has opened up the race for third place.
Spurs now find themselves only three points above fourth placed Manchester United and five points above sixth placed Chelsea.
With that in mind, this upcoming clash against Saints does feel like a must win encounter for Mauricio Pochettino’s side.
Southampton are in a similar predicament to their opponents. Ralph Hasenhuttl got off to a great start as the new man in charge of the club however, in recent weeks points have been hard to come by.
Three defeats in four games has seen Southampton dip in and out of the relegation zone. With Cardiff on a three-match losing run, Saints are currently two-points above the drop zone.
The recommendation in this game is to back the away side. Spurs were magnificent as they dismantled Dortmund in their Champions League tie and should have too much confidence and quality for this struggling Southampton side.
Tottenham to win - 10/11 bet365
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