The Spurs coach saw his side lose 2-1 to West Ham in the Capital One Cup following the sacking of Andre Villas-Boas and will be without Andros Townsend due to injury
A 5-0 Premier League thrashing by Liverpool at White Hart Lane on Sunday led to the sacking of Portuguese manager Andre Villas-Boas the following day, with caretaker boss Tim Sherwood overseeing a 2-1 home loss to West Ham in the Capital One Cup quarter-finals on Wednesday.
Spurs now sit seventh in the English top-flight but will hope to take advantage of Southampton's poor run of form, which has seen them fail to win any of their last five matches.
Kyle Walker captained Tottenham in midweek, deputising for the suspended Michael Dawson, and is confident that the club's poor run will end soon.
"Every one of us has to dig in – the fans, the staff, the players – because we're a great football team with great players, great fans," Walker told Tottenham's official website.
"We all need to stick together and come through this patch. We need to dig in and as I keep saying, it will be a good season, we're just having a blip at the moment."
Sherwood opted for a 4-4-2 formation against West Ham, partnering Emmanuel Adebayor with Jermain Defoe up front.
Adebayor rewarded him with a goal in his first start of the season and an attacking side – which featured Aaron Lennon and Andros Townsend on the wings – pleased Spurs fans.
Townsend will miss this game - and several more - after pulling his left hamstring in the match, while defender Jan Vertonghen [ankle] is also out.
Christian Eriksen [ankle], Vlad Chiriches [knee] and Younes Kaboul [thigh] are all in contention, however.
Successive defeats to Arsenal and Chelsea triggered a bad patch for Mauricio Pochettino's side, meanwhile, who drew 1-1 at Newcastle United last week.
Ninth-placed Southampton have not kept a clean sheet since October and look a shadow of the side that enjoyed such a strong start to the campaign.
Pochettino's men have scored 20 goals in their 16 Premier League matches – just Tottenham have scored fewer in the top half – and England striker Rickie Lambert has failed to repeat last season's form.
Lambert, who scored 15 league goals last term, has just four in 16 appearances in the current campaign.
Southampton are also without key players, with goalkeeper Artur Boruc [hand] and Victor Wanyama [calf] not expected to return until next year.
Defenders Danny Fox and Nathan Clyne [both hamstring] are also on the sidelines.
The two sides have met just twice since 2005, with Tottenham winning both fixtures last season.