The England defender pulled up clutching his hamstring 28 minutes into the contest at the King Power Stadium, and had to be replaced by Eliaquim Mangala.
28. Concerns for John Stones who's pulled up in pursuit of the ball. Looks like his hamstring and that could be John's game over— Manchester City (@ManCity) November 18, 2017
The 23-year-old initially appeared to be suffering discomfort in his hamstring during England's friendly with Brazil on Tuesday, and his injury on Saturday seemed to be a continuation of that problem.
In his post-match press conference, Pep Guardiola confirmed the 23-year-old is set for an extended spell on the sidelines.
"It is unfortunate for us and for John and I think he might be out for six weeks with that type of injury," Guardiola said.
"We don't have a lot of central defenders, but the spirit in the team – and with all the players – is good so we are going to find a solution."
Vincent Kompany made his own return from injury on Saturday and he looks set to be given a run of games in the centre of high-flying City's defence.
City would go on to defeat Leicester 2-0 thanks to goals from Gabriel Jesus and Kevin De Bruyne – the club's 10th straight league win.