In this study groundwater provenance, circulation, and rock interaction processes have been assessed by cross processing the spatial distribution of chemical and isotopic signatures in freshwater with the hydrogeological features of the coastal karst carbonate aquifer of Murgia, located in the southeastern end of Italy, along the Adriatic Sea. Thanks to widespread groundwater quality monitoring (major, minor, and trace-element analyses) and multi-isotopic measures of O, H, Sr, and B, some assumptions about complex groundwater circulation patterns, hydrogeological zoning, and water-rock interaction have been drawn. Three sectors have been distinguished into the Adriatic side of the Murgia aquifer all fed by two main recharge areas located on the most elevated, inner side of the aquifer. Each sector is characterized by different groundwater circulation patterns, residence time, and hydrogeochemical features. The water samples collected into the western sector evidence a certain degree of water-rock interaction, which allows us to assume long groundwater flow paths and residence time. On the contrary, the eastern sector of Murgia has been proven to be characterized by short residence times and a possible direct freshwater contribution even in the downstream course due to the massive presence of karst forms. Herein, the isotopic analysis of the water samples does not provide evidence of water-rock interaction. Finally, in the third, central sector, water infiltrated at different locations mixes flowing through relatively long paths even though not sufficient to allow groundwater to gain the rock's isotopic signature.