N-(1,3-Dimethyl butyl)-N'-phenyl-p-phenylenediamine (6-PPD) is a worldwide antioxidant commonly added to delay the thermo-oxidative degradation of tire rubbers. Unfortunately, 6PPD and its transformation product 6PPD-quinone are toxic to aquatic organisms (e.g., coho salmon). Herein, we explore the free radical scavenging activity and protective mechanism of melanin (MLN) on natural rubber's (NR's) oxidative resistance using molecular dynamics (MD) and quantum mechanical (QM) calculations. The relationship between the molecular structure and the chemical nature of the antioxidant molecules via transition state calculations is explored to unravel the reaction mechanisms of antioxidants interacting with peroxy radicals (ROO·) of NR with the estimation of reaction barriers. Following this, the radical scavenging activity of antioxidants was quantified via a hydrogen atom transfer mechanism and bond dissociation energy calculations. Parallel MD simulations were considered to study the interfacial interactions of antioxidant molecules with polymer chains and fillers with a quantifiable structure-property correlation. Given these results, the nanocomposite (NR-MLN-SiO2) with natural antioxidant melanin manifested outstanding antioxidant properties by preferentially bagging the ROO· radicals, thus improving NR's thermal-oxidative aging relative to 6-PPD. The MD results revealed that the intermolecular interactions at the NR/antioxidant interface benefited the antioxidant MLN to bind tightly to the NR in NR-MLN-SiO2 composite, thus exhibiting improved dispersion, O2 barrier properties, and thermo-oxidative stability, which could extend the service life of NR products (e.g., tires). In addition, as a sustainable antioxidant, MLN could replace toxic antioxidants like 6-PPD. More importantly, the QM/MD simulations provided a fundamental understanding of the mechanistic pathways of antioxidant molecules in NR composites, which are conducive to designing high-performance and sustainable green elastomers.