Permafrost degradation under a warming climate has altered hydrological and biogeochemical processes across the Arctic. Although increasing fluxes of weathering-derived ions (e.g., Ca2+, Mg2+, and SO42−) have been reported in Arctic rivers, the underlying mechanisms and hotspots within basins remain poorly understood due to limited analysis of environmental drivers such as climate and permafrost dynamics. We investigated long-term trends (1980–2022) in Ca2+, Mg2+, and SO42− concentrations in the Kolyma River in northeastern Siberia, and examined basin-wide changes in air temperature, precipitation, soil temperature, and active layer thickness. We found significant increases in ion concentrations, which were strongly correlated with rising subsurface soil temperatures (r = 0.61) and active layer deepening (r = 0.78) in the Yedoma-rich Kolyma Lowland. These findings, along with the concentration ratios, suggest that sulfuric-acid-driven carbonate weathering has intensified in the deeper part of the active layer—where previously frozen minerals become newly exposed—thereby enhancing ion discharges to rivers. Record-high concentrations were observed in 2020, when an extreme heatwave occurred, and produced exceptionally high subsurface soil temperatures (5.6°C; average 3.8 ± 0.6°C) during the thawed period (May–October) and active layer thicknesses (116.5 cm; average 100.3 ± 10.8 cm). These results underscore the sensitivity of Arctic river systems to heatwave-induced permafrost degradation, which rapidly intensifies subsurface weathering and solute mobilization. Given the widespread distribution of Yedoma across the Arctic, similar responses may occur in other watersheds. Continued monitoring of water chemistry and permafrost dynamics is essential to understand changes in Arctic river biogeochemistry.