A win for the home team could see Pep Guardiola's men go eight points clear of second-place Manchester United, with a game in hand, before the Red Devils travel to The Hawthorns to face off against strugglers West Bromwich Albion.
The visitors are, arguably, stuck in a rut and having the worst part of their season so far, with only two wins from their last five league games - one of which a defeat to 15th-placed Brighton & Hove Albion.
A win for Spurs could see them move into the top five - a disappointing stat when you keep in mind their impressive start to the season. A win would also boost their confidence after a classic FA Cup game against Everton knocked them out of the tournament.
A return for Agüero, after missing 11 games for COVID-related issues, could be on the cards. It seems too soon for the Belgium superstar, however.
Citizens may see Ruben Dias in defence after recovering from illness, while Rodri could be fit following his knock against Swansea City. Rodri's competition in midfield, Fernandinho, is likely to miss out with a thigh injury.
The only new concern for José Mourinho is Gareth Bale, who had a scan this week. Although the scan did not reveal any injury, the player is worried about a feeling so it will be touch and go as to whether the on-loan Real Madrid star plays.
"So he was not ready for the game [in midweek]. It's as simple as that. If he's ready for tomorrow he's selected for tomorrow," the Spurs boss stated in a press conference.
Man City: Ederson; Cancelo, Stones, Dias, Zinchenko; Bernardo Silva, Rodri, Gundogan; Mahrez, Foden, Sterling
Spurs: Lloris; Aurier, Sanchez, Dier, Davies; Hojbjerg, Ndombele, Sissoko; Lamela, Son, Kane
Ones to watch
Following a disappointing first season at the club for Tanguy Ndombele, the Spurs midfielder has sparked into life and has transformed Mourinho's midfield.
Davinson Sanchez proved midweek what the City defence will have to be wary of, with two goals against Everton. The first, a very well-taken header as the Columbian rose above everyone to bury the ball. And the second, an instinctive finish at the back post to give Spurs hope.
The whole City squad has been outstanding in recent fixtures which makes it difficult to pick a 'one to watch'. However, this game could be a game for Rodri to shine with the Spaniard going under the radar for most football fans.
Rodri will have a lot of work on his hands with the talented Ndombele to keep quiet and will have to help out at the back against a dangerous Heung-Min Son and Harry Kane partnership.
With De Bruyne still yet to return to full fitness, the pressure could be mounted onto İlkay Gündoğan's shoulders - City's Premier League leading goalscorer of the season so far.
Spurs' defence has been extremely shaky all season which will give the German confidence to get a goal or two after his performance at Anfield.
Spurs won the reverse fixture between the two sides all the way back in November, a miserable 2-0 scoreline against Guardiola and his men.
At home for City is a different story altogether, however. The Blues have won seven of the last 10 league meetings at the Etihad, only losing on 14th February 2016 - a daunting stat for Mourinho.
Most fans will remember this match-up for the famous (or infamous for City fans) Champions League quarter-final almost two years ago, in which Raheem Sterling's injury-time winner ruled out after a VAR check, and Fernando Llorente's scored a controversial goal with his hand.
That day a 4-3 aggregate scoreline saw a Spurs upset, and City dumped out of the Champions League.
How to watch
The game will be televised live on Sky Sports in the UK - Kick-off is at 17:30 GMT.