Acid mine drainage (AMD)—the strongly acidic and highly polluted effluents from mine sites—are generally managed via active or passive treatment. Active treatment strategies are effective but requires continuous input of energy, chemicals and manpower making them unsustainable in the long term. Because of this, passive treatment is explored as a more sustainable alternative especially for abandoned and legacy mines. Recent studies of the authors have explored the use limestone and waste materials like low-grade ores (LGO), fly ash (FA), and concrete wastes for AMD treatment and found that although these materials generated alkalinity individually, they could only partially remove sulfate (SO42−) and some heavy metals. To address this limitation, a mixed media approach using these four materials is proposed to neutralize the pH of AMD and maximize heavy metals (Cu, Fe, Mn, Ni, and Al) and SO42− removal. A total of twenty (20) mixtures of the four materials were identified based on the response surface methodology (RSM) experimental design. Laboratory-scale experiments using simulated AMD were performed to assess the performance of each mixture by monitoring the pH, oxidation-reduction potential (Eh), electrical conductivity (EC), metal concentrations, and SO42− concentration. Based on the results, three optimized mixed media compositions were identified in wt%: (i) 43% LGO, 40% limestone, 17% CW; (ii) 44% LGO, 51% limestone, 6% CW; and (iii) 89% limestone, 11% LGO. Overall, simulated AMD passively treated by the optimized mixed media compositions met the Philippine effluent standards except for SO42−. Simulated AMD treated by the optimized mixed media achieved pH values of < 9 and removal efficiencies for Cu, Fe, Mn, Ni, and Al of about 99%, 99%, 98%, 70%, and 96%, respectively.