Deep-sea mining can remobilize large amounts of inert metals from hydrothermal seafloor massive sulfides (SMSs) into bioavailable toxic forms that are dissolved in the water column, potentially impacting marine ecosystems. It is thus critical to assess the impacts of deep-sea mining on the reactivities and behaviors of crucial elements (e.g., Zn and Cu) and their isotopes during mineral leaching processes. To this end, we conducted leaching experiments using different SMS mineral types (CuFe rich, Fe rich, and ZnFe rich) to assess metal releases and the isotope fractionations of Zn and Cu. Significant correlations were observed between Ni, Cu, Zn, Cd, and Pb concentrations in leachates and the SMSs, suggesting that metal leaching into seawater depended on individual SMS metal content. The Zn and Cu concentrations in leachates varied greatly by both SMS type and the leaching time. Zn concentrations from ZnFe rich SMSs exceeded the recommended effluent limits set by the IFC World Bank and the USEPA. SMS ore leachates exhibited Cu and Zn isotope ratios distinct from those of Indian Ocean deep seawater. The isotope fractionation magnitude (Δore-seawater) of Cu was more pronounced than that of Zn, likely due to the redox process involved in the leaching processes. In contrast, the Zn isotope signatures in leachates conserve those of minerals, although slight isotope fractionations occurred in solution following the adsorption and precipitation processes of Fe-oxyhydroxides. Our findings confirm that leveraging the chemical and isotope signatures of toxic metals offers a valuable approach for assessing the extent of metal contamination of leachates and mine tailings stemming from deep-sea mining operations, concerning their influence on the surrounding water columns.