In Tibet, water resource has been less studied due to remote and harsh conditions. In this study, hydrochemistry and stable isotopes (δ²H, δ¹⁸O and ⁸⁷Sr/⁸⁶Sr) were employed to investigate the major factors affecting the hydrochemical process of groundwater and surface water in the lower reaches of the Yarlung-Zangbo River, southern Tibet. Groundwater and surface water were weakly alkaline and very soft to moderately hard water. The hydrochemical type of surface water is mainly Ca-HCO₃ (mainstream) and Ca-SO₄-HCO₃ (tributary), while the hydrochemical type of groundwater was mainly Ca-SO₄-HCO₃. Multivariate statistical analysis and Gibbs analysis proposed hydrochemical components were dominated by water-rock interaction. Ion ratio, saturation index, and Sr isotope revealed calcite dissolution and silicate weathering with local sulfide oxidation were involved in water–rock interaction. D-O isotopes indicated the recharge source was mainly derived from atmosphere precipitation. The entropy-weighted water quality index indicated surface water and groundwater reach the standard of drinking purpose in the lower reaches of the Yarlung-Zangbo River. The hydrochemical type varied regularly along the Yarlung-Zangbo River. The dissolution of carbonate rocks and local silicate weather and evaporate dissolution are the primary hydrochemical process along the Yarlung-Zangbo River. This study would provide a preliminary insight for hydrochemical process in the Yarlung-Zangbo River.