The exploration of novel geothermal systems, particularly those promising for electrical power generation, plays a fundamental role in incorporating new renewable sources into the energy matrix. Geothermal systems associated with volcanic calderas are considered ideal targets for exploration. This study focuses on the geochemical features of fluids from the Cerro Galán hydrothermal system, which is hosted within a major resurgent caldera with >3.5 Myr of magmatic evolution situated on the Southern Puna (Central Volcanic Zone of the Andes, NW Argentina). The main aim is constructing the first geochemical conceptual model and provide information on the geothermal potential of this interesting resource. The main hydrothermal reservoir consists of a NaCl aquifer with estimated temperatures up to 187 °C at depth. This reservoir is likely hosted within the fractured pre-caldera basement rocks, mainly including Miocene-Pliocene volcanic rocks and Proterozoic-Cambrian igneous and metamorphic rocks. The confinement of the deep reservoir is attributed to the deposits of the Toconquis Group and Cueva Negra Ignimbrite, along with the basal section of the Cerro Galán Ignimbrite, which exhibit low permeability due to hydrothermal alteration. The presence of a phreatic explosion crater near one of the hot spring-rich areas is likely indicating past over-pressurization of the hydrothermal aquifer, resulting from efficient sealing. Furthermore, the absence of anomalous soil CO2 flux values on the top of the reservoir, except where the thermal spring discharges are located, can be explained by an effective cap-rock layer. Deep circulation of meteoric water, enriched with atmospheric gases, receives inputs of magmatic fluids (∼11% of primordial helium), leading to the development of the hydrothermal NaCl aquifer. However, this deep fluid contribution might be underestimated due to significant crustal assimilation (up to 50%) involved in the magma genesis of the Cerro Galán Volcanic Complex, a process which modifies the He isotopic signature of the magmatic endmember. The hot springs, characterized by high flow rate (up to 459 m3/h) are positioned at the intersection between the caldera margins and the NNE-SSW oriented tectonic structures, suggesting favorable permeability conditions. The preliminary geothermal gradient for the Cerro Galán area is estimated at around 98–101 °C/km. Such a high gradient can be attributed to the considerable heat flux generated by the transcrustal plumbing system of the Cerro Galán caldera, which includes the shallow crystal mush reservoir (<4 km depth). The preliminary geothermal potential of this giant caldera was performed using the volumetric method along with Monte Carlo simulations. The results indicate a probable power production capacity of 2.09 MWe and 10.85 MWe at 90 and 50% confidence level, respectively. The results presented in this work constitute a foundational knowledge base to promote a more advanced exploration phase for the geothermal resource. Additionally to the local energy demand, lithium and other metal mining operations, which are operating independently from the National Interconnected System, could potentially be interested in power generation through binary cycles.