Unsaturated biopolymers (e.g., natural rubber (NR)) are highly vulnerable to thermo-oxidative degradation, which causes premature failure of NR products. As an indispensable antioxidant globally, 6PPD (N-(1,3-dimethyl butyl)-N′-phenyl-p-phenylenediamine) is employed to retard the thermo-oxidative aging of NR. Unluckily, 6PPD and 6PPD-quinone (an oxidative product of 6PPD) are highly harmful to aquatic and human life and, thus, obviously merit their replacement with sustainable and safer antioxidants for environmental protection. This study explored the use of natural antioxidant curcumin for NR-based polymer nanocomposites (PNCs). The combined experimental, molecular dynamics (MD), and quantum mechanics (QM) simulations are implemented to analyze the effect of isomeric forms of curcumin on the protective mechanism, oxidative stability, solubility, dispersibility, and diffusion in the NR matrix. The results revealed that both 6PPD and curcumin scavenged the free radical preferentially via a hydrogen atom transfer mechanism. The computed transition state energies show that curcumin's enolic form (i.e., Curcumin (E)) interacts preferentially with ROO. (peroxy) radicals of NR with the lower barrier energy compared to 6PPD and could protect the NR from thermo-oxidative aging. The MD simulations have shown that the interfacial interactions at the NRcurcumin interface resulted in stronger binding energies, thus improving solubility and dispersibility with lower mean square displacement than 6PPD. While the migration of antioxidants is necessary to replenish their concentrations at the tire surface, the higher diffusion rate may cause the physical loss of antioxidants and thus decrease the service life of NR-PNCs. Overall, the NR-PNCs loaded with natural antioxidant curcumin exhibited improved oxidative resistance and viscoelastic performance compared to PNCs made with 6PPD. Thus, as a sustainable and safe antioxidant, curcumin could open an essential avenue toward the substantial pollution abatement from accumulated waste NR products in making "Greener NR-PNCs.″