At present, the application of phytoremediation technology in the ecological remediation of heavy metal tailings is receiving more and more attention. In this study, the physiological and biochemical response and tolerance mechanism of woody plant Nerium indicum to Pb and Zn under different proportions of inorganic modifier calcium carbonate (C1: 5%, C2: 10%, C3: 15%) and organic modifier mushroom residue (M1: 10%, M2: 20%, M3: 30%) was compared. The results showed that the pH value has a trend of C group > M group > CK group and organic matter has a trend of M group > CK group > C group. Phosphatase activity and catalase activity has a trend of M group > C group > CK group, but catalase was more vulnerable to the calcium carbonate concentration. Both modifiers can promote the transformation of Pb, Zn, Cu, and Cd in tailings to more stable organic bound and residual states. However, the stabilization effect of mushroom residue is better, and its stability is Pb, Zn > Cd, Cu. Both modifiers can increase the biomass of Nerium indicum and the modification effect of mushroom residue is better than calcium carbonate. Pb/Zn content and accumulation in Nerium indicum organs showed root > stem > leaf in all groups. Compared with the CK group, the enrichment coefficient of Pb/Zn in C1 and M1 groups decreased, while the translocation factor of Pb/Zn in C1 and M1 groups increased. With the increase in modifier concentration, the enrichment coefficient increases about 1.75~52.94%, but the translocation factor decreases rapidly (20.01~64.46%). Clearly, both the calcium carbonate and mushroom residue amendment could promote the growth ability of Nerium indicum in lead–zinc tailings and strengthen the phytoremediation potential.