Permafrost degradation is altering biogeochemical processes throughout the Arctic. Thaw-induced changes in organic matter transformations and mineral weathering reactions are impacting fluxes of inorganic carbon (IC) and alkalinity (ALK) in Arctic rivers. However, the net impact of these changing fluxes on the concentration of carbon dioxide in the atmosphere (pCO₂) is relatively unconstrained. Resolving this uncertainty is important as thaw-driven changes in the fluxes of IC and ALK could produce feedbacks in the global carbon cycle. Enhanced production of sulfuric acid through sulfide oxidation is particularly poorly quantified despite its potential to remove ALK from the ocean-atmosphere system and increase pCO₂, producing a positive feedback leading to more warming and permafrost degradation. In this work, we quantified weathering in the Koyukuk River, a major tributary of the Yukon River draining discontinuous permafrost in central Alaska, based on water and sediment samples collected near the village of Huslia in summer 2018. Using measurements of major ion abundances and sulfate (SO₄^2-) sulfur (³⁴S/³²S) and oxygen (¹⁸O/¹⁶O) isotope ratios, we employed the MEANDIR inversion model to quantify the relative importance of a suite of weathering processes and their net impact on pCO₂. Calculations found that approximately 80% of SO₄^2- in mainstem samples derived from sulfide oxidation with the remainder from evaporite dissolution. Moreover, ³⁴S/³²S ratios, ¹³C/¹²C ratios of dissolved IC, and sulfur X-ray absorption spectra of mainstem, secondary channel, and floodplain pore fluid and sediment samples revealed modest degrees of microbial sulfate reduction within the floodplain. Weathering fluxes of ALK and IC result in lower values of pCO₂ over timescales shorter than carbonate compensation (∼10⁴ yr) and, for mainstem samples, higher values of pCO₂ over timescales longer than carbonate compensation but shorter than the residence time of marine SO₄^2- (∼10⁷ yr). Furthermore, the absolute concentrations of SO₄^2- and Mg²⁺ in the Koyukuk River, as well as the ratios of SO₄^2- and Mg²⁺ to other dissolved weathering products, have increased over the past 50 years. Through analogy to similar trends in the Yukon River, we interpret these changes as reflecting enhanced sulfide oxidation due to ongoing exposure of previously frozen sediment and changes in the contributions of shallow and deep flow paths to the active channel. Overall, these findings confirm that sulfide oxidation is a substantial outcome of permafrost degradation and that the sulfur cycle responds to permafrost thaw with a timescale-dependent feedback on warming.