Uzbekistan (Central Asia) is experiencing serious water stress as a consequence of altered climate regime, past over-exploitation, and dependence from neighboring countries for water supply. The Chirchik–Akhangaran drainage basin, in the Tashkent province of Uzbekistan, includes watersheds from the Middle Tien Shan Mountains escarpments and the downstream floodplain of the Chirchik and Akhangaran rivers, major tributaries of the Syrdarya river. Water in the Chirchik–Akhangaran basin is facing potential anthropogenic pressure from different sources at the scale of river reaches, from both industrial and agricultural activities. In this study, the major and trace element chemistry of surface water and groundwater from the Chirchik–Akhangaran basin were investigated, with the aim of addressing the geogenic and anthropogenic contributions to the dissolved load. The results indicate that the geochemistry of water from the upstream catchments reflects the weathering of exposed lithologies. A significant increase in Na+, K+, SO42−, Cl−, and NO3− was observed downstream, indicating loadings from fertilizers used in croplands. However, quality parameters suggest that waters are generally suitable for irrigation purposes, even if the total dissolved solid indicates a possible salinity hazard. The concentration of trace elements (including potentially toxic elements) was lower than the thresholds set for water quality by different regulations. However, an exceedingly high concentration of Zn, Mo, Sb, Pb, Ni, U, As, and B compared with the average river water worldwide was observed. Water in a coal fly-ash large pond related to the Angren coal-fired power plants stands out for the high As, Al, B, Mo, and Sb concentration, having a groundwater contamination potential during infiltration. Spring waters used for drinking purposes meet the World Health Organization and the Republic of Uzbekistan quality standards. However, a surveillance of such drinking-water supplies is suggested. The obtained results are indicators for an improved water resource management.