To address the pollution problem of acid mine drainage (AMD) characterized by high concentrations of Fe2+, Mn2+, and SO42−, a combination of coal gangue (CG) and sulfate-reducing bacteria (SRB) was employed. The effects of coal-gangue dosage, SRB inoculation concentration, and temperature on AMD treatment with coal-gangue-loaded SRB were determined through single-factor experiments and response surface methodology (RSM) experiments. By considering the principles of adsorption isotherms, adsorption kinetics, and reduction kinetics, the removal mechanisms of SO42−, Fe2+, and Mn2+ in AMD using coal gangue-loaded SRB in the the Haizhou open-pit mine was revealed. The results showed that the overall effectiveness of the four types of coal-gangue-loaded SRB in repairing AMD was as follows: 3# CG-loaded SRB > 2# CG-loaded SRB > 1# CG-loaded SRB > 4# CG-loaded SRB, with coal-gangue-loaded SRB in the the Haizhou open-pit mine showing the best performance. According to the RSM test, the optimum conditions for repairing AMD with coal-gangue-loaded SRB in the open-pit mine were a coal-gangue dosage of 52 g, SRB inoculation concentration of 11.7%, and temperature of 33.4 °C. The order of factors affecting the removal of SO42− and Fe2+ from AMD by SRB loaded on coal gangue was SRB inoculation concentration > temperature > coal-gangue dosage. For Mn2+, the order of influence was temperature > SRB inoculation concentration > coal-gangue dosage. In the process of repairing Fe2+ with coal-gangue-loaded SRB in the the Haizhou open-pit mine, the biological activity metabolism of SRB played a leading role, while the adsorption isotherm of Mn2+ followed the Freundlich model. The adsorption kinetics of coal-gangue-loaded SRB in the the Haizhou open-pit mine for Fe2+ and Mn2+ in AMD conformed to Lagergren’s second-order kinetic model, while the reduction kinetics of SO42− conformed to a first-order reaction model.