Land conversion and changing climate are expected to significantly alter tropical forest hydrology. We used a land surface model integrated with a river routing scheme to analyze the hydrological alterations expected in the Tapajós River basin, a large portion of the Brazilian Amazon, caused by two environmental drivers: climate and land use. The model was forced with two future climate scenarios (years 2026-2045) from the Earth System Model HadGem2-ES with moderate (+4.5 W/m 2 radiative forcing value in the year 2100 with respect to preindustrial levels) and severe (+8.5 W/m 2 ) representative atmospheric carbon dioxide pathways (Representative Concentration Pathways). We tested the sensitivity of our results to the uncertainty in future climate projections by running simulations with IPSL-CM5 (wettest scenarios) and GISS-E2 (driest scenarios). Human land use effects on vegetation were evaluated using a limited and an extreme deforestation scenario. Our analysis indicates that climate change is predicted to reduce river flows across seasons (up to 20%) and bring a considerable shift in flow seasonality toward a later onset (nearly 1.5 months) and increase in interannual variability. While land use change partially counteracts the climate-driven diminishing trend in river flows, it is expected to contribute to a further increase in interannual and intraannual variability. From a water management perspective, the overall reduction of river flows and their increased variability, combined with the shift and the shortening of the wet season, could potentially affect the productivity of the large hydropower systems planned for the region and the growing demand for agricultural and transport expansion.Plain Language Summary Climate and land use change are expected to heavily modify the water cycle. This is particularly true in tropical areas, where human-driven changes may completely alter river discharge. The Amazon is the largest of the remaining tropical forests. Increasing agriculture and livestock production have significantly altered land cover in the region. This pattern is projected to continue in the coming decades. The change in the Amazon's future is highly uncertain: the direct effects of climate and land use change are not well understood and the response also depends on complex Earth-atmosphere exchanges. We used computer models representing water and energy cycles over time to understand how environmental changes are likely to alter the discharge of the Tapajós River system in southeastern Amazon. By combining two climate and two land use scenarios, we found that climate change is expected to reduce the river flows in the basin, bringing a delay in the flow seasonality and increasing the overall variability. Land use change, conversely, is expected to cause an increase in flow magnitude and variability. Besides the serious environmental consequences, these findings have important implications for the management and development of water in this strategic area for Brazil's energy and food production.