This paper aimed at examining the climate variability and land-use change effects on streamflow and pollutant loadings, namely total suspended sediment (TSS), total nitrogen (T-N), and total phosphorus (T-P), in the Sesan, Sekong, and Srepok (3S) River Basin in the period 1981-2010. The well-calibrated and validated Soil and Water Assessment Tool (SWAT) was used for this purpose. Compared to the reference period, climate variability was found to be responsible to a 1.00% increase in streamflow, 2.91% increase in TSS loading, 11.35% increase in T-N loading, and 19.12% reduction in T-P loading for the whole basin. With regard to the effect of land-use change (LUC), streamflow, TSS, T-N, and T-P loadings increased by 0.01%, 3.70%, 10.12%, and 10.94%, respectively. Therefore, the combination of climate variability and LUC showed amplified increases in streamflow (1.03%), TSS loading (7.09%), and T-N loading (25.05%), and a net effect of decreased T-P loading (10.35%). Regarding the Sekong and Srepok River Basins, the streamflow, TSS, T-N and T-P showed stronger responses to climate variability compared to LUC. In case of the Sesan River Basin, LUC had an effect on water quantity and quality more strongly than the climate variability. In general, the findings of this work play an essential role in providing scientific information to effectively support decision makers in developing sustainable water resources management strategies in the study area.