Spurs have a good record at St James' Park, most recently winning 2-1 in the Premier League just under two years ago, but Newcastle have lost only three times at home this term.
The Lilywhites enter the match in high spirits after overcoming bitter rivals Arsenal 2-1 at the weekend thanks to a late goal from Toby Alderweireld.
Here, Sports Mole looks at how Jose Mourinho may set out his side against Newcastle.
The Portuguese is likely to revert back to a 4-3-3 of sorts on Wednesday, however, which could see Erik Lamela return to the side to provide some fresh legs.
Serge Aurier is expected to miss out following the death of his brother in the early hours of Monday, opening the door for fit-again Japhet Tanganga to slot in at right-back.
Dele Alli remains a fitness doubt after missing the last few games, while Eric Dier is still suspended.