In the Friuli Venezia Giulia (FVG) Region (NE Italy), a significant portion of the water supply relies on groundwater derived from karst aquifers, which are widely present in this territory. These aquifers are recharged through abundant rainfall, which in the pre-Alpine belt reaches 3,300 mm/year. Unfortunately, due to the high permeability of carbonate rocks, the concentrated recharge of water and its rapid infiltration, the swift transport in karst conduits, and the limited self-purification capacity of the water body, such water resources are particularly susceptible to contamination and, therefore, must be vigilantly monitored. Within the framework of a collaboration between the University of Trieste and the Geological Survey of the FVG Autonomous Region, a total of 130 karst aquifers were mapped; 16 of these were studied in detail, and their intrinsic vulnerability was assessed by using a modified COP method. The investigated aquifers have shown very high vulnerabilities, 85% of their total area falling into the highest 3 of 6 vulnerability classes: ‘High’ (31%), ‘Very high’ (41%), and ‘Extreme’ (13%). The maximum vulnerability is found in karstified limestones affected by the highest rainfall and lacking of soil and vegetation cover, in the areas at the lowest altitudes where the depth to groundwater reaches its minimum, and in the areas of maximum concentration of flow, where the water sinks into the subsoil through sinkholes, caves, and swallow holes.