Jordan Ridley, Matt Guelfi, Jake Kelly, Sam Durham and Alec Waterman will all miss Saturday night's contest at Marvel Stadium.
Hawthorn livewire Chad Wingard is also a late withdrawal from what would've been his 200th game, replaced by Connor Macdonald.
The Bombers' sick quintet have been replaced by the four emergencies - Brayden Ham, Kaine Baldwin, Brandon Zerk-Thatcher and Aaron Francis - as well as Devon Smith.
Alastair Lord has also been included in the squad and will make his AFL debut as the medical substitute.
"Late in the week we had a handful of players succumb to illness and we've given them every opportunity to be fit for tonight's game," Essendon football manager Josh Mahoney said.
"As a result, we've had to make five forced changes, which includes debutant Alastair Lord being named as medical sub.
"Devon Smith, who wasn't originally listed as an emergency, has also come into the side after putting his hand up to be available.
"The plan for Dev was for him to complete a mini-preseason to build up the muscles around his knee.
"Given the situation, Dev put his hand up to play and we are looking forward to him contributing tonight."
Running defender Lord was pick No.46 at last year's draft and has impressed at VFL level.
Essendon's blows come after Jake Stringer (hamstring) and Nik Cox (ankle) were ruled out during the week.
The Bombers are desperate for a win to reignite their season after a horror 1-6 start.
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