Having already recovered from an ankle operation, McDonald is set to go under the knife again after suffering a stress fracture in his fibula.
The 23-year-old returned to football in April with restricted minutes in the VFL following off-season surgery on the ankle injury suffered in last year's preliminary final.
It was the same injury that ultimately forced his substitution halfway through the grand-final loss to Brisbane.
Kicking three goals in his return game against North Melbourne's reserve side, McDonald reported soreness after his second match, with subsequent scans showing a stress reaction.
He remains sidelined indefinitely, though Cox won't rule McDonald completely out.
"You're always hopeful," Cox said on Thursday.
"Once a surgeon goes in there and looks at exactly what's wrong and fixes what he has to and then gives you a time frame, we'll put a little bit more perspective into it, so hopefully it's not a long one.
"But as soon as you're having surgery, it's not a two or four-week injury, so we've got to support Logan.
"It's the best thing for him to get back playing his best football, so that's the sole focus of the surgery and why we're going down that path."
Swans skipper Callum Mills has returned to training from plantar fasciitis injury, but Cox says the club hasn't put a definitive date on his return.
"One thing we've learnt over the period is that if you plan exact dates of when they're coming back, it becomes really tough," Cox said.
"We just try and look at, every week, what he does - how much has he done? What does he need to improve on?' And we'll do the same again.
"He trained twice last week. He'll train again today and over the weekend."
Cox has opted against calling up midfielder Taylor Adams, returning from a hamstring injury as Sydney (3-5) prepare to play Essendon (4-3).
Adams has only played in one game this season, featuring in opening round.
Defender Ben Paton returns to the side from a calf strain, replacing suspended Lewis Melican.
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