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The Tonle Sap is the most fertile and diverse freshwater ecosystem in Southeast Asia, receiving nurturing water flows from the Mekong and its immediate basin. In addition to rapid development in the Tonle Sap basin, climate change may threaten natural flow patterns that sustain its diversity. The impacts of climate change on river flows in 11 sub-basins contributing to the Tonle Sap Lake were assessed using the Soil and Water Assessment Tool (SWAT) model to quantify the potential magnitude of future hydrological alterations. Projected river flows from three General Circulation Models (GFDL-CM3, GISS-E2-R-CC and IPSL-CM5A-MR) for three time horizons (2030s, 2060s and 2090s) indicate a likely decrease in both the wet and dry season flows. The mean annual projected flow reductions range from 9 to 29%, 10 to 35% and 7 to 41% for the 2030s, 2060s and 2090s projections, respectively. Moreover, a decrease in extreme river flows (Q₅ and Q₉₅) was also found, which implies there could be a decline in flood magnitudes and an increase in drought occurrences throughout the basin. The results of this study provide insight for water resources planning and adaptation strategies for the river ecosystems during the dry season, when water flows are projected to decrease.