McDonald has missed the past two matches, after suffering the injury against Carlton.
Football operations general manager Chris Connolly said McDonald could be sidelined for up to two matches.
“James has a significant hamstring tear,” Connolly told melbournefc.com.au.
“This has slowly progressed over the past few weeks and we’re hopeful he’ll return to football over the next one to two weeks.”
Midfielder/forward Colin Sylvia, who has also been sidelined for the past two matches with a toe injury, will train this week with a view to returning against the Saints.
Emerging ball-winner Jordan Gysberts, who claimed 26 and 25 disposals in his first two matches in rounds 10 and 11, will miss a couple of weeks with a back injury.
In better news for the Demons, youngsters Luke Tapscott and Sam Blease are set to play their first match this season.
Tapscott, selected at No.18 in last year’s NAB AFL Draft, has missed the year after undergoing hip surgery.
He is a chance to line up in the Casey seniors, although Blease, who is in his second season, has been mooted for the VFL reserves.
Ruckman Max Gawn, selected at No.34 in last year’s NAB AFL Draft, is now only 1-2 weeks away, after missing the year so far with a knee injury.
Bur rookie Rhys Healey continues to have a frustrating run with injury.
He will miss the next four to five weeks, after aggravating has hamstring.
Daniel Hughes, who has played two matches this season, will face a fitness test, due to an ankle injury.
Forward Ricky Petterd (shoulder) and ruckman John Meesen (ankle) remain sidelined long-term.
Round 14 injury list