Police executed multiple search warrants on Tuesday at a home in Keysborough, and an eight-hectare property in Devon Meadows, in Melbourne's southeast.
Officers chased eight suspects who fled the large property as police arrived.
All eight suspects were arrested, with five men aged 26-49 charged with multiple offences including cultivating a large commercial quantity of cannabis.
They appeared in Melbourne Magistrates' Court on Wednesday, where they were remanded to reappear at a later date.
"This investigation highlights the sophisticated measures alleged offenders use to conceal illegal drug activity," Sergeant Josh Gordon added.
"This is a significant seizure of cannabis, preventing millions upon millions of dollars' worth from hitting the streets."
Police spent two days searching the property which uncovered the alleged illicit crop, with officers dismantling the set up that was growing in gardening igloos.
About 4500 plants of varying maturity were removed from the property, with an estimated street value of $15 million.
The plants will be destroyed following forensic examination by a botanist.
Police also seized a firearm, and quantities of amphetamines, cocaine, ammunition and cash from the property.
Three men aged 32, 37 and 41 were released on intent to summons for cultivating a large commercial quantity of cannabis, while a man and woman, both aged 33, were spoken to and released pending enquiries.
Police anticipate further charges.
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