Geochemical and isotopic characterization of groundwater and lake-water samples were combined with water and total dissolved solids balances to evaluate sources of groundwater quality deterioration in eastern Hetao Basin, Inner Mongolia, China. Groundwater quality is poor; 11 of 13 wells exceed drinking-water guidelines for at least one health-based parameter and all wells exceed aesthetic guidelines. The well water is largely derived from Yellow River irrigation water. Notably high uranium concentrations in the Yellow River, relative to world rivers, suggest groundwater uranium and other trace elements may originate in the river-derived irrigation water. Complex hydrostratigraphy and spatial variation in groundwater recharge result in spatially complex groundwater flow and geochemistry. Evapotranspiration of irrigation water causes chloride concentration increases of up to two orders of magnitude in the basin, notably in shallow groundwater around Wuliangsuhai Lake. In addition to evapotranspiration, groundwater quality is affected by mineral precipitation and dissolution, silicate weathering, and redox processes. The lake-water and TDS balances suggest that a small amount of discharge to groundwater (but associated with very high solute concentrations) contributes to groundwater salinization in this region. Increasing salinity in the groundwater and Wuliangsuhai Lake will continue to deteriorate water quality unless irrigation management practices improve.