The England captain attempted to make a robust challenge on Fabian Delph close to the sideline, but came off second best.
Kane left the Tottenham Hotspur Stadium wearing a protective boot and Mauricio Pochettino admitted the injury sustained to his left ankle could well be season-ending.
He told BT Sport: “We need to check tomorrow but it looks the same, a similar issue.
“Very sad, very disappointed, and it’s going to be tough for the rest of the season.
“We hope it’s not a big issue but there’s not much time to recover. He’s twisted his ankle and we will see how he reacts in the next few hours.”
With the 25-year-old off the pitch, Heung-min Son struck with just 12 minutes of normal time remaining to give Spurs a vital 1-0 lead over City heading into the return leg next week at the Etihad.
But the succession of ankle injuries Kane has picked up throughout his career will be a real concern to Pochettino, who has been forced to play without his talisman already this season.
Below, talkSPORT.com examines Kane’s injury history to determine how Spurs cope without their star striker and if there is a serious issue to address.