An approach, combining several geochemical methods, was used to determine the groundwater properties and components of a hypogene karst system, where sampling is restricted only to the spring sites, and with a limited number of available sampling locations. Radiogenic isotopes (3H, 14C) were used to constrain the groundwater mean residence time and separate different groundwater components. Noble gases, stable isotopes of water (δ18O, δ2H), dissolved inorganic carbon (δ13C) and dissolved sulfate (δ34S, δ18O), and major ion and trace element composition were used to identify the source of water, its chemical evolution and water–rock interactions, as well as to identify the contribution and composition of endogenic gases. This approach was applied to three low-temperature thermal springs located in Mariovo (North Macedonia) associated with fossil hypogene caves, previously identified by morphological and geochemical studies of caves and cave deposits. Based on the obtained results, the main studied springs represent an output part of a regional hypogene karst groundwater system with a deep-circulating (~1 km), old (~15 ka), thermal (≥60 °C) water, which mixes with young (<50 years), cold (<14 °C) and shallow epigene karst groundwater. The output parts are structurally controlled, at the interception of low topography and deep faults, along which the groundwater interacts with deep-seated gases, dominantly CO2 of metamorphic origin (δ13C of +4.5‰ VPDB), with some contribution of mantle helium. The thermal karst groundwater interacts at depth with volcanic rocks from the nearby Neogene-Quaternary volcanic complex, as well as with metamorphic basement rocks and granitoids.