Quantitative understanding of potential changes in streamflow and sediment load is complicated by uncertainty related to land use change projections, which is characterized by a high uncertainty in terms of demand (quantity) and location of changes (spatial distribution). We simulate the Sesan, Srepok, and Sekong Rivers (3S), the most important tributaries of the lower Mekong River, with the Soil and Water Assessment Tool (SWAT) to investigate the implications of conversion of forest to agricultural lands. Multiple land use transitions in the 3S basin are projected using the Land Change Modeler. The uncertainty in land use projection was addressed using an ensemble forecasting approach for 2060, combining (a) three land demand scenarios, (b) two transition potential modeling approaches (i.e., approach to create maps of the likelihood for areas to transition from one land use type to another), and (c) retaining or not protected areas. Land demand leads to the greatest uncertainty in land use change projections. Transition potential modeling approaches do not make much difference in the total change, but can result in spatial variations of change. Retaining protected areas can contribute significantly to uncertainty in land use change projections. Decrease in annual streamflow of the 3S basin varied from 3% to 21%, and changes in annual sediment outflux from the basin ranged from −8% to 249% for simulated scenarios. Land use demand uncertainty results in the highest streamflow and sediment load changes and can thus have major consequences for water and sediment management strategies in areas undergoing rapid development.