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The great rivers that flow from the southern Tibetan Plateau (TP) affect billions of people in the downstream countries of Asia. Understanding of the hydrological variability of these rivers is still limited, however, because of the lack of long-term streamflow records. Tree-ring width chronologies from six sites are applied to reconstruct annual streamflow of the Salween River, the last remaining large free-flowing transboundary river draining the southern TP, and a critical water source for countries of Southeast Asia. Response function analysis shows that precipitation is the main factor limiting the radial growth of the sampled trees. Linear regression of annual (September-June) Salween River streamflow on the first principal component of tree-ring chronologies explains 53.4% of the streamflow variance, 1958-2011, and yields a reconstruction for the interval 1500-2011 CE. A tally of droughts and wet periods emphasizes the severity of droughts before the start of the gauged records, and a tendency toward wetter conditions in recent decades. Regional temperature is negatively associated with the reconstructed streamflow. Cold wet summers controlled by the Asian summer monsoon are responsible for an increasing trend in streamflow over the last decades. Reconstructed hydrological change is linked to the history of mainland Southeast Asia through the impact of water shortages on Burma society. In particular, prolonged periods of low flow of the Salween River coincide with the falls of the Toungoo Empires and the First Anglo-Burmese War. This tree-ring reconstruction provides a long-term perspective on hydrological changes in the Upper Salween River Basin that can give insight for sustainable water management on the TP and in Myanmar.