Oxidative weathering of sulfide minerals in sedimentary rocks releases carbon dioxide (CO2) into the atmosphere. In permafrost zones, this could be a positive feedback on climate change if it increases with warming, yet sulfide oxidation rates and their temperature response remain unknown over large spatial and temporal scales. We analyze a 60-year sulfate concentration dataset from catchments across the Mackenzie River Basin. Sulfate fluxes increased by 45% in the mainstem with 2.3°C of warming, and the temperature sensitivity suggests that continental-scale CO2 fluxes could double by 2100. The largest increases occur in catchments with geomorphic settings which act to rapidly expose rocks through physical weathering and thermokarst processes. Comparisons with a weathering model suggest that warming can increase reaction rates, and changes in the exposure of minerals with warming are also required. Future warming across vast Arctic landscapes could further increase sulfide oxidation rates and affect regional carbon cycle budgets.