Abstract: By using statistical methods, ensemble empirical mode decomposition, wavelet analysis, hydrological models and other methods, the laws and driving mechanisms of runoff changes, historical floods and droughts, and the trend of runoff changes under the impact of future climate changes in the headwaters region of the southwestern rivers were investigated on the basis of in-depth analysis on meteorological and hydrological data, lake cores data, tree rings data, and climate model prediction data in this study. The results showed that the annual streamflow in the Three-River Headwaters region showed a significant upward tendency during the past 50 years, and the annual streamflow in the Yarlung Zangbo River basin showed an insignificant downward trend except the Niyang River basin. Climate change was the major factors to affect the streamflow changes in the Three-River Headwaters region, Yarlung Zangbo River basin and Nujiang River basin, and precipitation played the most important role for these changes. Results indicated that the variations between wet and dry periods are different in these rivers. In the mid reach of the Yarlung Zangbo River, flood events in wet periods frequently occurred in the early and late Holocene, but relatively less occurred in the Mid Holocene. The reconstruction runoff time series of the Nujiang River basin over the past 500 years includes 10 wet periods and 10 dry periods. The variations between wet and dry periods in the region are mainly controlled by the monsoon circulation and ENSO activities. The continued global warming in the next 15—60 years will increase the average annual runoff of the Southwestern rivers by 6%—14% compared with the past 30 years. Meanwhile, the extreme runoff presents the characteristics of "drier and drier, wetter and wetter" and ecological factors have a non-negligible effect on runoff changes in the future.