To tackle the degradation of sealing performance in nitrile butadiene rubber (NBR) seals due to material aging during long-term service, this study integrates experimental and molecular simulation methods to elucidate the aging mechanism. Experimental results reveal that the contents of C=C and C=O functional groups significantly decrease during aging, accompanied by enhanced hydrophobicity and increased crosslink density of NBR, indicating that crosslinking reactions dominate the aging process with the participation of C=C and C=O groups. Quantum mechanics (QM) and molecular dynamics (MD) simulations further demonstrate that α-H, C=C, and C≡N groups are preferentially oxidized due to their low bond energies. The oxidation of NBR generates unstable epoxy intermediates, which undergo chain scission to form ketones, aldehydes, and ultimately crosslinked structures. Using a multi-dimensional evaluation system based on bond dissociation energy (BDE), solubility parameter (Δδ), and migration coefficient (MSD), four antioxidants (4010NA, 4010, MC, and BHT) were screened. BHT emerges as the optimal choice, exhibiting superior free radical scavenging ability (BDE = 346.3 kJ/mol), good matrix compatibility (Δδ = 2.95), and anti-migration properties. The MD-based screening method established herein provides a theoretical basis for designing antioxidant systems in high-performance rubber materials, facilitating the development of advanced rubber products.