Acidification and metal mobilization linked to sulfide mineral oxidation pose an urgent risk to water quality and ecosystem health in thawing permafrost regions. Over the past six years, we have observed large increases in sulfate and metal concentrations and fluxes coupled with notable pH decreases in several headwater streams in the Tombstone Waters Observatory, Yukon, Canada. Field observations and satellite imagery reveal the emergence of acidic seepage zones characterized by extensive vegetation dieback and ochreous mineral precipitation. This seepage can exhibit pH < 3 and sulfate concentrations up to 5 g L-1, with metal (e.g., Fe, Al, Mn, Ni, Zn) concentrations ranging from 10s to 100s of mg L-1 and often exceeding water quality criteria. Subsequent pH buffering along groundwater discharge and stream mixing zones drives extensive precipitation of Al and Fe (oxyhydr)oxide and (hydroxy)sulfate phases, which influence metal transport and are visible many kilometers downstream. Notable increases in sulfate concentrations for major downstream rivers (e.g., Klondike, Ogilvie, Peel) show that coupled biogeochemical and hydrological processes in headwater catchments can have widespread impacts. Moreover, the growing occurrence of acidic seepage zones and ochreous mineral precipitates suggests impacts of permafrost thaw and sulfide mineral oxidation represent a substantial long-term risk to subarctic stream chemistry. Our ongoing research at the Tombstone Waters Observatory aims to advance understanding of the complex coupled processes influencing stream water chemistry in thawing permafrost regions.