Former Coventry City youngster Jonson Clarke-Harris could be out for up to nine months.
A holder of City's youngest ever player record, Clarke-Harris, damaged his anterior cruciate ligament whilst playing for Rotherham United in a 7-0 win over Parkgate.
"It is a real blow firstly to Jono and obviously for the club," Millers boss Alan Stubbs told the Millers club website.
"The injury came from a nothing kind of challenge, but unfortunately our worst fears have now been confirmed.
"We will do everything we can to try and get Jono back as soon as possible.
"We know roughly the timescale for a return is between six and nine months with this kind of injury."
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Former City loanee Chris McGuire scored for Oxford United in their 2-1 defeat to Leicester City.
Former City loanee Matt Mills scored for Nottingham Forest in a 2-0 win at Port Vale.
Former City loanee Chris Dagnall scored for Crewe in a 4-0 win away to Nantwich Town.