Defender James Perch has been ruled out for the season after a scan has revealed a fractured skull.
The 35-year-old suffered the injury during a training session last month following an innocuous aerial challenge.
The former Newcastle United player had been in excellent form in his first four games of the season for the Stags.
Manager Nigel Clough said: “It’s devastating news for both James and ourselves. It’s a massive blow.
“As we’ve said all along, we cannot take any chances with this type of injury and are being completely guided by the specialists.
“We’ll do everything we can to support James throughout his rehabilitation.”
James Perch said: “I feel gutted to learn that I won't be able to step on to the pitch again this season and help the team.
“I also feel so disappointed not to play in front of the Stags’ supporters again in 2021-22, on their first season back inside the ground, and was hoping for a really productive campaign for my hometown club.
“I’d like to thank the medical staff at the club, the manager and his staff, my family and the Stags’ fans for their support and well wishes.
“I’ll remain as positive as possible and as one of the experienced players in the squad, I’ll be doing my utmost to support the boys in and around the training ground on a daily basis.”
The club will offer its unreserved support to James throughout his rehabilitation period.