The 33-year-old has missed the past four matches with a hamstring injury and has not played since round 11 against Carlton.
Up until that point, McDonald was one of Melbourne’s best performers and displayed the type of form that netted him back-to-back club champions in 2006-07.
But McDonald must pass a fitness test first, before being given the all clear.
The Demons will also be without young-gun Jack Grimes for another two matches. Grimes sustained a hamstring injury against St Kilda in round 14.
Impressive young midfielder Jordan Gysberts (back) will be out for one more match, as will versatile tall Stef Martin (hip).
Half-back/midfielder James Strauss (knee) is another two weeks away.
But there is some positive news looming with giant ruckman Max Gawn on the verge of playing his first match associated with the club.
The first-year Demon suffered a knee injury last year and now faces a fitness test later this week to see if he will play for Casey in the VFL.
Rookies Michael Newton (quadriceps), Daniel Hughes (ankle) and Rhys Healey (hamstring) look set to miss two more matches each.
Ricky Petterd, who re-signed for another two years with the club last week, is out for the rest of the season with a shoulder injury.
Ruckman John Meesen remains sidelined indefinitely with a ankle problem.
Round 16 injury update
Max Gawn (knee) - test
Jack Grimes (hamstring) - 2 weeks
Jordan Gysberts (back) - 1 week
Rhys Healey (hamstring) - 2 weeks
Daniel Hughes (ankle) - 1-2 weeks
Stefan Martin (hip) - 1 week
James McDonald (hamstring) - test
John Meesen (ankle) - indefinite
Michael Newton (quadriceps) - 2-3 weeks
Ricky Petterd (shoulder) - season
Jake Spencer (back) - test
James Strauss (knee) - 2 weeks
