The haul is reported to be one of the largest-ever drug busts in Europe with an estimated street value of €240 million.
Italian authorities say they have confiscated 4.3 tons of cocaine with a street value of more than €200 million.
The Guardia di Finanza say the haul is one of the largest-ever drug busts in Europe and has dealt a blow to Colombia’s feared Gulf Clan.
The cocaine was seized in the northeastern Italian port city of Trieste following a yearlong investigation that also involved US Homeland Security and Spanish National Police.
Authorities have also issued 38 arrest warrants for alleged international drug trafficking in Italy, Slovenia, Croatia, Bulgaria, the Netherlands and Colombia.
The undercover operation issued a "strong blow to one of the most important Colombian narcotics groups,” Italian anti-mafia investigators said in a statement.
Authorities estimate that criminal groups paid €96 million for the cocaine, which would have been worth €240 million on the Italian market.
As part of the operation, undercover agents infiltrated a drug smuggling chain that operated across Italy in the northern regions of Veneto and Lombardy, the Lazio region including Rome, and the southern region of Calabria, home of the 'Ndrangheta mafia.
Key suspects both at the intermediary and international levels were identified in 19 "controlled deliveries," the statement added.
Along with the drug, agents also seized €1.8 million in cash as well as some vehicles allegedly used for trafficking, including a big-rig truck.
The Clan del Golfo cartel is one of Colombia's largest criminal gangs and operates a network across 28 different countries.
Last month, the group's alleged leader Dairo Antonio Úsuga David -- also known as "Otoniel" -- extradited from Colombia to the United States after his arrest in October.
Úsuga is accused of "leading a continuing criminal enterprise" and "participating in an international conspiracy to manufacture and distribute cocaine".