Flanders was helped from the field after being injured in the second quarter of the 52-point defeat at Marvel Stadium on Thursday night.
St Kilda on Friday confirmed the 24-year-old had ruptured his Achilles and will miss the rest of the season.
It was another sour note to a disappointing night for the Saints (5-7), who failed to kick a goal in the first half against the high-flying Hawks (8-1-3).
GWS forward Jake Riccardi will miss at least two months, part of a massive double injury blow for the Giants.
Riccardi underwent surgery for ankle syndesmosis after injuring himself in the dying stages of the Giants' 78-point win over the Brisbane Lions.
He joins defender Jack Buckley, who went down in the first quarter against the reigning premiers with a hamstring injury.
Heading to Alice Springs to face a plucky Melbourne side, GWS are already without spearhead Jesse Hogan (hip) and fellow forward options Darcy Jones (knee), Xavier O'Halloran (ankle) and Cody Angove (hamstring).
GWS captain Toby Greene and Jake Stringer have been the only forwards to feature in all 11 games so far as the club manages a raft of injuries.
Giants coach Adam Kingsley described Riccardi's return timeline as "loose".
"I'd imagine it's going to be a normal syndesmosis recovery, which is two months," Kingsley said.
"It happened in the last 40 seconds of the game, which I think is the fourth time we've lost someone within the last five minutes of a game and the second time inside the last minute.
"That's pretty disappointing for us. He's an important part of our team, as we know."
Buckley will spend at least four weeks on the sidelines after Kingsley initially hoped the star defender had only suffered hamstring soreness.
At worst, Buckley could be out for six weeks with a moderate-grade hamstring strain.
Buckley has already missed two games this season through injury.
"I didn't think it was that serious. He certainly didn't present as that serious," Kingsley said.
"That's the danger with me coming out and suggesting timelines, particularly before MRIs are done, it can be way off the mark.
"That's a bit disappointing for Jack. He's been quite interrupted this season with bits and pieces, calves, hamstrings, concussions.
"He'll recover strongly, and hopefully next time back in he gets a bit of continuity, a good run at it and can help build into finals hopefully."
GWS will at least have some reprieve, with All-Australian defender Sam Taylor returning for his first game of the season.
Taylor suffered a high-grade hamstring strain while representing Western Australia in State of Origin in February.
"Having not played a game in three months is going to take a little while to get back to his full strengths, but he'll slot in," Kingsley said.
"We'll be a better back line with him, but he hasn't played for a long time ... so he'll be a little bit underdone in a sense.
"I just figured when he was ready, we'll play him. And he's ready this week. I don't think we need to be careful with him."
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