Climate variability influences both water quantity and quality in lakes and rivers, e.g., shifts in salinity caused by changes in the evaporation/precipitation ratio. However, knowledge about climate and human influences on water quality in some regions is scarce, which causes uncertainty when evaluating water resources and developing water management plans. We measured the chemical composition and stable isotope values (δD and δ18O) in water samples from the Ili-Balkhash Basin, arid Central Asia, to investigate factors that control hydrologic processes in the area, and explore how the arid environment influences local hydrochemistry and water resources. Isotope values in lake waters (−24.1‰ [δD] and −1.5‰ [δ18O]) are enriched relative to river waters (−84.6‰ [δD] and −12.4‰ [δ18O]), indicating that lake waters experience intense evaporation. In the upstream Ili River, waters with lowest δD and δ18O values are supplied mainly by glacial ice and snow melt, whereas lower reaches of the river are affected increasingly by evaporation and human water extraction. Waters of the Ili River and other small rivers that drain to Lake Balkhash are chemically similar, and of the Ca-HCO3 type. Gibbs diagrams indicate that mineral weathering is the key process that controls river water chemistry. On average, carbonate and silicate weathering contribute 55.1% and 26.7%, respectively, to the total dissolved ion load in the river waters, illustrating the strong control that regional geology exerts on streamwater chemistry. In contrast, lake waters are characterized as Na-Cl type, which results mainly from evaporation and some evaporite dissolution. Weathering in the area is controlled by climate, i.e. precipitation and temperature. Moreover, a negative correlation between lake water total dissolved solids and d-excess, and a systematic increase in chemical concentrations and stable isotope values downstream in the Ili River, reflect the fact that arid climate conditions promote evaporation and affect water quality. PCA analysis and mass balance calculation of water chemistry suggests that humans contribute only 6.6% of the major ion load to waters, which display increasing concentrations in the middle and downstream regions. There, effects of human-mediated weathering and transport of salts from agricultural irrigation are reinforced by higher temperatures and evaporation.