Based on the results of 15 years of research on the physical and chemical parameters of 11 occurrences of thermal and mineral water in the extended area of the spa town of Vrnjačka Banja, diverse hydrochemical types of water have been identified, originating from different lithological formations (serpentinite, schist, marble, etc.). Currently, the total amount of abstracted thermo-mineral water is close to 70 L/s, with water temperatures up to 33.8 °C. However, interpretation of collected data indicates that the chemical composition of the mineral water is not exclusively related to the mineralogical composition of the host rock, i.e., aquifer material. To better understand the genesis of these waters, multivariate statistical analysis was undertaken in combination with hydrochemical interpretation of different ionic ratios. This approach revealed the existence of three distinct clusters of thermal and mineral waters: (1) low temperature, low mineral content and mild alkaline; (2) slightly acidic, with a moderate mineral content and elevated iron and fluoride concentrations; and (3) thermal, rich in CO2, with elevated mineral content and iron, manganese and fluoride concentrations. Two primary hydrogeochemical processes, which influence the composition of the thermo-mineral waters, were also identified: dissolution of serpentinite rocks and dissolution of schists, both enhanced by the presence of CO2 gas, circulating through fault zones. Estimates of available geothermal energy suggest a significant potential for expanding current uses of thermal waters of this most popular spa center in Serbia.