There is a substantial amount of carbon stored in the permafrost soils of boreal forest ecosystems, where it is currently protected from decomposition. The surface organic horizons insulate the deeper soil from variations in atmospheric temperature. The removal of these insulating horizons through consumption by fire increases the vulnerability of permafrost to thaw, and the carbon stored in permafrost to decomposition. In this study we ask how warming and fire regime may influence spatial and temporal changes in active layer and carbon dynamics across a boreal forest landscape in interior Alaska. To address this question, we (1) developed and tested a predictive model of the effect of fire severity on soil organic horizons that depends on landscape-level conditions and (2) used this model to evaluate the long-term consequences of warming and changes in fire regime on active layer and soil carbon dynamics of black spruce forests across interior Alaska. The predictive model of fire severity, designed from the analysis of field observations, reproduces the effect of local topography (landform category, the slope angle and aspect and flow accumulation), weather conditions (drought index, soil moisture) and fire characteristics (day of year and size of the fire) on the reduction of the organic layer caused by fire. The integration of the fire severity model into an ecosystem process-based model allowed us to document the relative importance and interactions among local topography, fire regime and climate warming on active layer and soil carbon dynamics. Lowlands were more resistant to severe fires and climate warming, showing smaller increases in active layer thickness and soil carbon loss compared to drier flat uplands and slopes. In simulations that included the effects of both warming and fire at the regional scale, fire was primarily responsible for a reduction in organic layer thickness of 0.06 m on average by 2100 that led to an increase in active layer thickness of 1.1 m on average by 2100. The combination of warming and fire led to a simulated cumulative loss of 9.6 kgC m−2 on average by 2100. Our analysis suggests that ecosystem carbon storage in boreal forests in interior Alaska is particularly vulnerable, primarily due to the combustion of organic layer thickness in fire and the related increase in active layer thickness that exposes previously protected permafrost soil carbon to decomposition.