The raids were the culmination of an investigation code named Pollino that was launched in 2016 against the 'Ndrangheta criminal group on allegations of cocaine trafficking, money laundering, bribery and violence, said Eurojust, the European prosecution agency that fights cross-border organized crime, which co-ordinated the operation.
At least 90 people were arrested, and more than three tons of drugs and millions of laundered money were seized across Italy, Germany, Belgium, the Netherlands and Luxembourg.
The 'Ndrangheta, a mafia organisation that operates out of the Calabria region of southern Italy, is one of the world's largest crime syndicates and thought to make billions of euro through cocaine trafficking every year. Cocaine and ecstasy pills also were seized in the raids.
"It's nearly a cliche, but the operation carried out today confirms again the great danger of the 'ndrangheta, not just in drug trafficking, where it's the undisputed leader, but (also) in the financial sphere", said Francesco Ratta, a top police official in the southern Italian region of Calabria.
"Today, we send a clear message to organised crime groups across Europe", Filippo Spiezia, vice president of the EU's judicial agency Eurojust, told reporters in The Hague.
The "unprecedented" crackdown on the group based in Calabria, southern Italy, came just a day after Italian police arrested the new boss of the separate Sicilian mafia. "There are thousands of people who should be arrested and billions of euros that should be seized".
Officials hailed Wednesday's operation as a serious blow to the group.
In January police arrested almost 170 people, including mayors and businessmen and local administrators, in similar raids across Italy and Germany.
According to reports, Italian restaurants and ice cream parlors were used to launder money as well as several businesses and homes across four countries.
The raids follow Tuesday's operation against the Sicilian Mafia in Palermo, which resulted in the capture of the syndicate's newly elected leader, 80-year-old jeweller Settimo Mineo, in addition to 45 other suspects.
Dutch NOS television said the 'Ndrangheta were mainly active in the Netherlands in drug smuggling through the country's huge flower export market.
Mineo, 80, was detained along with at least 45 others just before he was due to be appointed official heir to notorious mafia boss Toto Riina who died in prison past year.