Millions of euro in laundered money was seized at the businesses and homes raided across the four countries, officials said, and several "high-ranking" members of 'Ndrangheta are believed to have been among those arrested.
It has surpassed Sicily's Cosa Nostra and the Naples-based Camorra in influence thanks to control of the cocaine trade and is the sole mafia organisation to operate on all continents, according to anti-mafia prosecutors.
Germany's Federal Criminal Police Office (BKA) also said raids had been carried out on the Spanish island of Mallorca.
The 'Ndrangheta - which derives its meaning from the Greek word for "heroism" - is made up of numerous village and family-based clans in Calabria, the rural, mountainous and under-developed "toe" of Italy's boot.
Deputy Prime Minister Luigi di Maio hailed the operation as "one of the biggest blows inflicted on the mafia" by the Italian authorities.
A total of 200 million euros ($227 million) of criminal money, as well as 140 kg of ecstasy pills and more than 3,000 kg of cocaine were seized.
In January police arrested almost 170 people, including mayors and businessmen and local administrators, in similar raids across Italy and Germany. The AD said a year ago that Dutch police had introduced a special police unit completely dedicated to fighting mafia activities on Dutch soil.
The 'ndrangheta "is the most important organized crime group in the world", said Gen. Alessandro Barbera, who commands the investigative unit of Italy's financial police corps. A BKA spokeswoman told the German press agency (dpa) on Wednesday that the investigation focused on the state of North Rhine-Westphalia, but premises in Munich had also been searched.
Italian anti-mafia prosecutor Federico Cafiero De Raho said the operations would affect the 'Ndrangheta's drug trafficking operations around the world, including in Colombia, Ecuador, and Brazil.
Dutch outlet NOS said that the 'Ndrangheta is known to operate its drug smuggling through the country's vibrant flower-trading industry.
European Parliament President Antonio Tajani, who is Italian, sent "congratulations" to the police forces involved, adding: "Europe fights 'Ndrangheta criminal groups".
The Wednesday arrests came just a day after the authorities announced the arrest of Settimo Mineo, 80, the presumed new boss of the Cosa Nostra.
Just under half of the suspects were detained in Italy.
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