It will also be the first time the German faces Spurs manager Jose Mourinho in the opposite dugout.
Both clubs have spent time at the summit in the early parts of the season, however, neither side have been able to capitalise on their good start and have seen theirselves slide down the Premier League table.
Ultimately, the poor form cost former manager Frank Lampard his job, while the pressure is beginning to mount on Mourinho, as his side have registered only two wins in their past nine league outings.
It is an opportunity for Tuchel to announce his arrival in the league and transform the West London club's fortunes, building on the 2-0 win in his previous fixture over Burnley.
Mourinho will have to lift his team's spirits, following their disappointing 1-0 loss to Brighton & Hove Albion, as Tottenham eye up the race for a Champion's League spot.
Out-of-favour midfielder, Dele Alli, who was linked with a move away during the January window will miss this fixture due to a tendon problem.
Arguably Spurs' most creative spark, Tanguy Ndombele is a doubt heading into the game, after being forced off away to Brighton.
Both Sergio Reguilon and Giovani Lo Celso are ruled out through injury, Mourinho confirmed Serge Aurier will return to the matchday squad - following reports of a dressing room row in the loss to Liverpool last week.
Much to Tuchel's delight, he appears to have a fully fit squad at his disposal, as he seeks his first away victory in charge.
Hakim Ziyech was left out of the previous matchday squad, but Tuchel pointed out it was due to him needing a rest so he could make a return, alongside N'Golo Kante who has recovered fully from a hamstring injury.
It will be interesting to see whether Tuchel opts to keep faith in the out-of-form Timo Werner, with Christian Pulisic and Kai Havertz pushing for a place in the starting XI.
Ones to watch
Tottenham: Heung-Min Son
Without Kane to lead the line, the responsibility falls on Heung-Min Son going forward, the attacker has recorded 12 goals and six assists in the league.
He struggled against Brighton without Kane, with the two forming a telepathic-like partnership this season, combining throughout the course of the campaign.
This is likely to suit the Korean international as he will be able to operate off his preferred left-wing position.
Vinicius has a great physical presence and will be able to hold the ball up comfortably, dropping in deep to pick up the ball, this could create space for Son to exploit in behind where he is most dangerous.
Son's record against Chelsea is unimpressive, scoring only twice in 10 league appearances against them, he will need to be at his firing best for Spurs to come out on top.
Chelsea: Callum Hudson-Odoi
Callum Hudson-Odoi has been long spoken about as a youngster with great potential, destined to hit the heights in Europe, however, it is yet to materialise for the England international.
He has never been able to hold on to a regular starting position at Chelsea and that looks to be the major factor in his hindered development.
The introduction of Tuchel is a fresh opportunity for the wide-man, one he has grabbed with both hand, winning the Man of the Match award in the opening two games of the new era.
Deployed in an unorthodox right wing-back position, he has exceeded exceptions with his performances.
Going forward he has been a very useful creative outlet, looking extremely dangerous when in and around the opposition box, but he has also looked comfortable in a defensive capacity.
It remains to be seen if Tuchel favours him over a natural defender such as Reece James in a clash such as this, but his performances so far bear resemblance to the success of Victor Moses under Antonio Conte.
Tottenham (3-4-3): Lloris; Alderweireld, Dier, Rodon; Doherty, Hojbjerg, Sissoko, Davies; Bergwijn, Vinicius, Son
Chelsea (3-4-3): Mendy; Azpilicueta, Silva, Rudiger; Hudson-Odoi, Kovacic, Kante, Alonso; Mount, Giroud; Pulisic
How to watch
Tottenham Hotspur vs Chelsea will kick off at 8pm GMT on Thursday 4th February 2021, and is available to watch, live from the Tottenham Hotspur Stadium on BT Sport 1.