The rapid development of the Greater Mekong Subregion (GMS) makes it essential to understand the major mechanisms controlling the streamflow, especially for the Lancang-Mekong River (abbr. Mekong River). We used instrumental annual streamflow data (1960–2007) from Chiang Saen hydrological station and several gridded hydroclimatic datasets to explore the hydroclimatic evolution of the Mekong River, together with its driving mechanisms. We found that changes in the Mekong streamflow are consistent with precipitation changes, and the Mekong is thus a precipitation-dominated river that is susceptible to the effects of ongoing climate change. The instrumental record of Mekong annual streamflow is closely related to hydroclimatic changes, especially those related to moisture, within the area from the Hengduan Mountains to the Chiang Saen Station. Based on these gridded records, we extended the Mekong annual streamflow record to cover 1891–2021 using nested multiple linear regression fitting. The fitted streamflow explained up to 57.6 % of the instrumental changes and it indicates that the major 2019 drought was not unique over the past century. Despite extremely low precipitation and high temperatures, it is likely that the effects of drought can be mitigated via hydraulic engineering regulation. Climatological analyses showed that the Mekong annual streamflow is driven by the El Niño-Southern Oscillation (ENSO) and the Indian Ocean Dipole (IOD), which is consistent with observed quasi-interannual cycles of 3–4 years. A multi-model ensemble of CMIP6 revealed that the Mekong annual streamflow will experience an upward trend in the future, accompanied by the more extreme impacts of ENSO and the IOD.