The livelihood of inhabitants from rural agricultural valleys in the arid Arica and Parinacota Region, northernmost Chile, strongly depends on water from high altitude rainfall and runoff to lower elevation areas. However, elevated arsenic, boron, and other potentially harmful elements compromise water quality, especially in rural areas. Samples (n = 90) of surface, underground, cold, geothermal springs, and treated and raw tap water were studied to assess water quality and to determine the main geochemical controls on water composition, origin, and geochemical evolution along dominant flowpaths. Water from major river basins across the region (Lluta, San Jose, Codpa-Chaca, Camarones and Altiplanicas) were collected for hydrogeochemical analysis of a suite of major and trace elements, δD and δ18O. Our new dataset was supplemented by hydrochemical data (n > 1500 data points) from secondary sources. Results show that 72% of the collected samples had As >10 μg/L (WHO drinking water provisional guideline) and affected 44% of the studied waters used for drinking (n = 32). Based on Chilean irrigation guidelines, elevated salinity (EC > 0.75 mS/cm) affected 80% of sampled waters, which were also impacted by high B (89% > 0.75 mg/L), and As (31% > 50 μg/L). Water composition was strongly controlled by geothermal water and freshwater mixing in high altitude areas. Magnitude and fate of As and B concentration was determined by the geothermal input type. Highest As (~21 mg/L) was associated with circum-neutral Nasingle bondCl waters in Camarones basin, while lower As (~5 mg/L) with acid SO4 waters in Lluta basin. Additionally, evaporative concentration and sediment-water interactions were shown to control the level of As in surface and groundwaters downstream. This works provides a comprehensive analysis and a conceptual model of geochemical controls on regional water compositions, contributing to better understanding the geochemical processes underpinning the water quality challenges in northern Chile.