Rodrigo Bentancur has been handed a seven-match ban by the Football Association, which begins this weekend, for comments that he made about teammate Son Heung-min a few months ago. Spurs have since lodged an appeal against the length of the ban.
Micky van de Ven, Richarlison and Wilson Odobert are also ruled out with hamstring injuries, the former of whom is still a "good couple of weeks" away from making a return, while Cristian Romero - whose wife has just had a baby daughter - is doubtful with a foot problem.
The potential absence of Romero could see Ange Postecoglou select Ben Davies alongside Radu Dragusin at centre-back, with Destiny Udogie and Pedro Porro - once on the books at Man City - operating as full-backs.
In the absence of Bentancur, who started in Tottenham's 2-1 defeat to Ipswich Town last time out, Yves Bissouma or James Maddison could be recalled to start in centre-midfield alongside Dejan Kulusevski and Pape Matar Sarr.
Son Heung-min, along with Kulusevski, scored in a 3-3 draw away against Man City last season, and he is expected to start in attack alongside Brennan Johnson and Dominic Solanke.
Tottenham Hotspur possible starting lineup: Vicario; Porro, Dragusin, Davies, Udogie; Kulusevski, Bissouma, Sarr; Johnson, Solanke, Son