Rodrigo Bentancur was handed his start since February in the 2-1 defeat to Aston Villa last weekend after recovering from an ACL injury, but the midfielder is now facing another "couple of months" on the sidelines after sustaining an ankle injury following a strong challenge from Matty Cash.
The Uruguayan joins a packed treatment room that includes James Maddison (ankle), Micky van de Ven (hamstring), Richarlison (pelvic), Manor Solomon (knee), Ivan Perisic (knee), Ryan Sessegnon (thigh), Ashley Phillips (ankle), Alfie Whiteman (ankle) and Pape Matar Sarr (muscle).
Spurs will also be without Cristian Romero for the trip to Man City as he will serve the third and final game of his three-match ban, but Yves Bissouma is available to return from his suspension and will likely start in centre-midfield alongside either Pierre-Emile Hojbjerg or Giovani Lo Celso, who scored the opener against Villa last time out.
Ange Postecoglou will consider sticking with the same back four that lined up against Villa, with full-backs Emerson Royal and Ben Davies potentially starting in central defence ahead of Eric Dier, while Pedro Porro and Destiny Udogie operate as full-backs.
In attack, Brennan Johnson, Dejan Kulusevski and Bryan Gil are all expected to retain their places in behind central striker Son Heung-min, who has scored six of his eight Premier League goals this season away from home.
Tottenham Hotspur possible starting lineup: Vicario; Porro, Emerson, Davies, Udogie; Bissouma, Lo Celso; Johnson, Kulusevski, Gil; Son