<p>Sulfate-rich wastewater poses significant environmental and health risks, as the presence of heavy metals amplifies toxicity through synergistic effects, complicating treatment processes. An UASB reactor was operated for eight months to investigate the synergistic effects of co-metals on in-situ sulfide control under varying COD/SO₄²⁻ ratios and hydraulic retention times (HRTs). The combined toxicity of nickel (Ni2+) and copper (Cu2+), each at an individual concentration of 150&#xa0;mg/L, reduced methane production by 51.3%; however, metal precipitation strategies effectively mitigated this toxicity, resulting in improved sulfide control and enhanced methane production. At relatively low COD/SO₄²⁻ ratios (1-0.5), methanogenic and sulfate-reducing bacteria (SRB) demonstrated syntrophic acetate oxidation, with a maximum usable Cu²⁺ concentration of 0.825 mmol/L. The maximum sulfide precipitation of 683.81&#xa0;mg/L was achieved at a COD/SO₄²⁻ ratio of 0.5 and a 12-h HRT. The system demonstrated high efficiency in removing both COD (92.7%) and sulfate (94.5%) while achieving an energy recovery rate of 42.38 mmol CH₄/L. With nickel and copper acting synergistically, the reactor demonstrated stable performance, achieving enhanced sulfate and COD removal efficiency while effectively mitigating sulfide toxicity and improving methane production. These findings highlight the technical feasibility of metal supplementation for in-situ sulfide control and the optimization of anaerobic treatment of sulfate-rich wastewaters.</p> Graphical abstract <p></p>