High latitudes are predicted to continue warming at higher rates than the global average, with major implications for northern basins where concomitant deglaciation, permafrost thaw and vegetation shifts are expected. The Mackenzie River Basin, a globally significant basin, drains headwaters in the glaciated Canadian Rockies to the Arctic Ocean and is mostly underlain by permafrost. Here, we present scenarios of future change using the MESH distributed hydrological-cryospheric land surface model. MESH was forced with bias-corrected, downscaled RCM forcings and parameterized with a deep subsurface profile, organic soils, and glaciers. The model was validated against discharge, snowpack, and permafrost observations and used to simulate the hydrology and permafrost dynamics over the 21st century under the RCP8.5 climate change scenario with projected land cover change. The results show rapidly increasing rates of permafrost thaw; most of the basin will be permafrost-free by the 2080s. By late century, river discharges shift to earlier and higher peaks in response to projected increases in precipitation, temperature, snowmelt rates, despite increases in evapotranspiration from longer snow-free seasons. Baseflow discharges increase in winter, due to higher precipitation and increased basin connectivity from permafrost thaw resulting in enhanced groundwater flow. Subsurface moisture storage rises slightly but the liquid water fraction increases dramatically, increasing sub-surface runoff and river discharge. Canadian Rockies deglaciation reduces summer and annual discharge in the Athabasca and Peace headwaters. Downstream and northward of the mountain headwaters the direct impacts of climate change on river discharge dominate over those of changing land cover and glaciers.