The response of chemical weathering to climate could be examined in a way by investigating seasonal changes in river geochemistry. Here, we determined the major elements, δ13C of DIC, 87Sr/86Sr, δ7Li, and δ26Mg of monthly time-series water samples at the Daojieba Hydrological Station in lower reach of the Nujiang River over a hydrological year. During high-flow seasons, the dissolved 87Sr/86Sr, δ7Li, and δ26Mg exhibit comparatively high values. 87Sr/86Sr ratio, together with δ13C of DIC, Si/Ca ratio, and pH value of river water, indicate an enhanced silicate weathering contribution to river dissolved load, and river δ7Li is impacted by secondary mineral formation-related fractionation during these periods. Similar to the 87Sr/86Sr ratio, δ26Mg of river water is indicative of a dominant source control. The positive relationship between Mg/Na ratio and δ26Mg value suggests that the prior weathering of Mg-rich silicate minerals could be important for elevated δ26Mg and Mg/Na molar ratio during high-flow seasons, while the Mg isotope fractionation signal can be seen when runoff increases dramatically. During low-flow seasons, river 87Sr/86Sr and δ26Mg values evolve to a carbonate weathering signal, whereas river δ7Li reflects a more congruent silicate weathering, and these changes point to the obvious influence of geothermal water in these periods. The covariations of δ7Li, δ26Mg, and discharge are observed. Changes in runoff can significantly impact the isotopic composition of Li and Mg by changing the hydrological flow path, in which dominant reactions of mineral dissolution and secondary mineral formation vary. This study highlights the hydrological control on Li and Mg isotopic compositions of the Nujiang River water, which could be considered the dominant control of monsoon climate on weathering processes in high-relief river basins at a short-term scale.