Mikheyev will require surgery, Keefe said Monday.
Mikheyev left Saturday's pre-season game against the Ottawa Senators and did not return, after taking a hit into the boards.
This isn't the first time Mikheyev has dealt with injuries. During the 2019-20 season, he missed a significant period of time after a skate blade caused a wrist laceration, which required immediate surgery.
The 27-year-old played 54 games during the 2020-21 season, where he recorded seven goals and 10 assists.
The Maple Leafs open their regular season on Wednesday against the Montreal Canadiens at Scotiabank Arena.