The Bombers' tumultuous season plagued by injuries continues to worsen after losing star playmaker Nic Martin (knee) and midfielder Will Setterfield (foot) long-term in Saturday night's ugly loss against Richmond.
Essendon confirmed on Wednesday young midfielder Elijah Tsatas had also joined the injury list after straining his hamstring during the defeat.
Rising forward Nate Caddy and midfielder Ben Hobbs were also injured, but are expected to only miss a week.
Essendon will equal the most debutants in a season in the AFL era - 13 - when mid-season draftee Liam McMahon plays against the Giants at Marvel Stadium on Thursday night.
Archie Perkins, Jade Gresham, Vigo Visentini, Dylan Shiel and Matt Guelfi also come into the side amidst a whopping six changes, with veteran ruckman Todd Goldstein rested.
Bombers coach Brad Scott was almost lost for words when detailing the injury crisis after the Richmond game, but was more upbeat a day out from facing the Giants.
"A five-day break, there's no time to be getting distracted from what I need to do," Scott said on Wednesday.
"I do have the utmost confidence in the people who are looking at our program. There's no doubt we will relocate resources to that (medical conditioning) space.
"We know better than anyone this year how important it is to get your players fit and available.
"It's hard not to be really frustrated, almost exasperated, just devastating seeing players like Nic Martin and Will Setterfield suffer really serious injuries.
"It's been a perfect storm of a whole range of different injuries all coming together at once.
"There are moments, don't get me wrong, where we all - including me - feel sorry for ourselves, but we've got to bounce out of that really quickly."
Martin became the fourth Bomber to injure their ACL this season, joining Nick Bryan, Lewis Hayes and Tom Edwards.
Sam Draper will also be sidelined for up to 12 months after rupturing his achilles in April.
Essendon will have 11 first-choice players sidelined against GWS - Martin, Setterfield, Caddy, Hobbs, Draper, Darcy Parish, Jye Caldwell, Kyle Langford, Ben McKay, Harry Jones and Zach Reid.
The Bombers will be spared GWS at their best, with Coleman Medallist Jesse Hogan and star midfielder Josh Kelly to miss the trip to Melbourne.
But GWS veteran Stephen Coniglio will make his long-awaited AFL return, having overcome a glute complaint stemming from a nerve issue suffered earlier this season.
The Giants also recalled Max Gruzewski and Toby McMullin.
Essendon will be facing up to former star Jake Stringer in Giants colours for the first time.
Stringer booted 207 goals in 123 games for the Bombers before seeking a move to GWS last off-season.
After a frustrating start to his time in western Sydney, the 31-year-old hit some serious form against Geelong last week with four goals.
"I played seven or eight years with some of those guys that have gone down with long-term injuries. My heart goes out to them," Stringer said of Essendon's injury crisis."We won't be going out Thursday night taking them lightly.
"We'll be going out there thinking they're full-strength and getting after it.''
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