The painkiller has been described as the "fighter drug" as it is known to be popular among terrorists for its ability to dull pain and suppress fatigue.
The haul is estimated to be worth 50 million euros ($58 million), and was found following a police crackdown sparked by the discovery of a similar shipment in Genoa in May.
Investigators believe the ISIS planned to sell the tablets to their foot soldiers for the equivalent of two euros a tablet.
"According to the information shared with foreign investigative sources, the traffic of Tramadol is directly handled by IS to finance terrorist activities planned and carried out across the world," the court of Reggio Calabria said.
Part of the money raised from the sales would also go "to subsidize terrorist groups and extremists operating in Libya, Syria and Iraq," it said in a statement.
The court said the catch had been possible thanks in part to the DEA, the US Drug Enforcement Administration.