The major ion and the multi-isotopic composition (87Sr/86Sr, δ11B, δ34S(SO4) and δ18O(SO4)) of groundwater from the Central Depression in northern Chile is investigated to identify the origin of groundwater solutes in the hyper-arid core of the Atacama Desert. The study area is between the Cordillera de Domeyko and the Central Depression, at latitudes 24-25°S, and is characterized by near-zero air moisture conditions, rare precipitation and very limited runoff. Groundwater composition varies from Ca-HCO3 to Ca, Na-SO4 type below elevations of 3400 m a.s.l. The rCl/rBr ratio of meteoric waters and groundwater overlap, but significantly increase in the aquifer as salinity goes up due to evapoconcentration far from the Domeyko Cordillera. The wind-displaced dust originating in the Central Depression (87Sr/86Sr: 0.706558-0.710645; δ34S(SO4): 0 to +4‰) affects the precipitation composition in the highest parts of the Domeyko Cordillera (87Sr/86Sr: 0.706746-0.709511; δ34S(SO4): +1 to +6‰), whose δ34S(SO4) and δ11B values are greatly different from marine aerosols, discarding its contribution to dust at this distance inland. Sr and S isotopic values in groundwater indicate a strong relation with three main geological units: i) Paleozoic rocks contribute high radiogenic strontium isotope ratios to groundwater (0.707011-0.714862), while sulphate isotopic composition is probably acquired from atmospheric dust (>- 1.4‰), ii) Jurassic marine limestones contribute low-radiogenic strontium isotopic ratios to groundwater (<0.70784), while sulphate can be related to oxidized sulphides that change the isotopic signatures of sulphur (<-1.2‰), and iii) mixed salts in the Atacama Gravels contribute lower radiogenic strontium isotopic ratios and sulphate to groundwater (87Sr/86Sr: <0.707324; δ34S(SO4): +0.1 to +7.7). These three processes reflect water-rock interactions. The δ11B of groundwater generally up to +13‰, does not increase along the regional groundwater flow path, discarding fractionation by interaction with clays. These results improve the understanding of the groundwater evolution in hyper-arid systems through a new conceptual model.