In this study, the Providing Regional Climates for Impacts Studies (PRECIS) and the Regional Climate Model (RegCM) system as well as the Variable Infiltration Capacity (VIC) macroscale hydrologic model were integrated into a general framework to investigate impacts of future climates on the hydrologic regime of the Athabasca River basin. Regional climate models (RCMs) including PRECIS and RegCM were used to develop ensemble high-resolution climate projections for 1979–2099. RCMs were driven by the boundary conditions from the Hadley Centre Global Environment Model, version 2 with Earth system configurations (HadGEM2-ES); the Second Generation Canadian Earth System Model (CanESM2); and the Geophysical Fluid Dynamics Laboratory Earth System Model with MOM (GFDL-ESM2M) under the representative concentration pathways (RCPs). The ensemble climate simulations were validated through comparison with observations for 1984–2003. The RCMs project increases in temperature, precipitation, and wind speed under RCPs across most of the Athabasca River basin. Meanwhile, VIC was calibrated using the University of Arizona Shuffled Complex Evolution method (SCE-UA). The performance of the VIC model in replicating the characteristics of the observed streamflow was validated for 1994–2003. Changes in runoff and streamflow under RCPs were then simulated by the validated VIC model. The validation results demonstrate that the ensemble-RCM-driven VIC model can effectively reproduce historical climatological and hydrological patterns in the Athabasca River basin. The ensemble-RCM-driven VIC model shows that monthly streamflow is projected to increase in the 2050s and 2080s under RCPs, with notably higher flows expected in the spring for the 2080s. This will have substantial impacts on water balance on the Athabasca River basin, thus affecting the surrounding industry and ecosystems. The developed framework can be applied to other regions for exploration of hydrologic impacts under climate change.