The assets snatched from the 'Ndrangheta mafia, which controls much of Europe's cocaine trade, included more than 1,500 betting shops, 82 online gambling sites and almost 60 companies, as well as numerous properties, the police said.
Prosecutors issued arrest warrants for 28 people suspected of running the gambling empire and placed 23 others either under house arrest or ordered them to check in with the police.
The crew is believed to have been headed by mobster Mario Gennaro, who made his way up through the mob in the southern region of Calabria from local to regional chief because of the gambling ring's success.
The 'Ndrangheta is considered the most powerful crime syndicate in Italy, having surpassed Sicily's Cosa Nostra and the Naples-based Camorra thanks to the wealth it has amassed as the principal importer and wholesaler of cocaine produced in Latin America and smuggled into Europe via north Africa and southern Italy.
Profits from the trade, which is worth billions, were laundered through the gambling empire.
The gang "recycled an enormous amount of 'dirty' money through the use of gaming accounts assigned to willing or unwitting people", police said in a statement.
"They bypassed the laws governing this sector, accumulating significant profits that were then reinvested in the acquisition of new companies and licences to further expand their activities."
Eleven of the companies seized were based abroad, in Austria, Malta, Romania and Spain.
Interior Minister Angelino Alfano described the sting in Reggio Calabria as "a serious blow to the 'Ndrangheta".
The name 'Ndrangheta comes from the Greek for courage or loyalty and the organisation's tight clan-based structure has made it hard to penetrate.
In a triumph for anti-mafia hunters, dozens of alleged mobsters linked to the group were detained at the end of last year in and around Milan, Italy's business capital, on charges of criminal association and extortion.
Police released secretly-filmed footage of men undergoing initiation into "Santa" (holy) membership, whereby promoted mobsters swore allegiance to their new "wise brothers" and took an "oath of poison" under which they vow to kill themselves should they ever betray fellow clan members.
A separate sting in January led to the seizure of a notebook written in a hieroglyphic-style code which detailed the initiation rites and the 'Ndrangheta's hierarchical structure from "piciotto" (foot soldier) up to Godfather.
It also detailed the clan's own mystical account of how its structure and "code of honour" came into being as a result of three knights landing on an island off Sicily after being banished from Spain for avenging the honour of their raped sister.
The gambling operation came just two weeks after authorities seized goods worth 1.6 billion euros from a Sicilian mafia family, which included 33 companies, hundreds of houses, villas and buildings, 80 bank accounts, 40 insurance policies and over 40 vehicles.