GWS veteran Brett Deledio and ruckman Dawson Simpson are likely to miss the rest of the AFL season, while small forward Toby Greene will be racing the clock to return before finals.
Deledio (calf), Simpson (ankle), Greene (hamstring) and Sam Taylor (hamstring) all suffered injuries during the Giants' 105-point win over Carlton.
The expansion club's biggest win of the year has proven their most costly.
GWS are yet to put a timeframe on Deledio's latest calf setback, but fitness guru David Joyce admitted the club will be "pretty conservative" given the former Richmond star's chronic calf problems.
"He's had well documented issues with both calves in the past and unfortunately this just adds to that," Joyce said.
Simpson will spend at least eight weeks on the sidelines because of a fractured ankle, meaning his 2018 campaign is over.
Greene and Taylor may not play again before September.
GWS are in ominous form, having won eight of their past nine games, but coach Leon Cameron is now forced to reshuffle his magnets yet again in what has been an injury-cursed campaign.
The Giants have also confirmed hard-running midfielder Tom Scully, who has been sidelined since round two because of a broken ankle, will play no further part in this season.
The good news for Cameron is that Tim Taranto (knee), Dylan Shiel (hamstring), Sam Reid (knee), Ryan Griffen (hamstring) are in the mix to return against Adelaide in Canberra on Saturday night.
The quartet is likely to be available, provided they get through the club's main training session on Wednesday.
Deledio has managed a total of 16 games in his two seasons at the Giants.
The 31-year-old's previous stint on the sidelines was almost three months. He hurt his hamstring in round six then tweaked his calf while recovering.
Greene, who also spent three months on the sidelines this year because of a foot injury, returned in round 17 and added plenty of potency, confidence and class in GWS's forward line.
Taylor has impressed in defence during his maiden season, while Simpson's absence will also create a giant hole for Cameron to fill.
Simpson has been a revelation since his round-14 recall, allowing ruckman Rory Lobb to spend more time in attack.
"He's torn the ligaments on the inside of his ankle ... because of the way the foot has fallen, he's managed to fracture his ankle on the other side," Joyce said.
"The big fella is in remarkable spirits considering what he's been through."
