In this study, we applied a computer-based protocol to identify novel antioxidant agents that can reduce oxidative stress (OxS), which is one of the main hallmarks of several disorders, including cancer, cardiovascular disease, and neurodegenerative disorders. Accordingly, the identification of novel and safe agents, particularly natural products, could represent a valuable strategy to prevent and slow down the cellular damage caused by OxS. Employing two chemical libraries that were properly prepared and enclosing both natural products and world-approved and investigational drugs, we performed a high-throughput docking campaign to identify potential compounds that were able to target the KEAP1 protein. This protein is the main cellular component, along with NRF2, that is involved in the activation of the antioxidant cellular pathway. Furthermore, several post-search filtering approaches were applied to improve the reliability of the computational protocol, such as the evaluation of ligand binding energies and the assessment of the ADMET profile, to provide a final set of compounds that were evaluated by molecular dynamics studies for their binding stability. By following the screening protocol mentioned above, we identified a few undisclosed natural products and drugs that showed great promise as antioxidant agents. Considering the natural products, isoxanthochymol, gingerenone A, and meranzin hydrate showed the best predicted profile for behaving as antioxidant agents, whereas, among the drugs, nedocromil, zopolrestat, and bempedoic acid could be considered for a repurposing approach to identify possible antioxidant agents. In addition, they showed satisfactory ADMET properties with a safe profile, suggesting possible long-term administration. In conclusion, the identified compounds represent a valuable starting point for the identification of novel, safe, and effective antioxidant agents to be employed in cell-based tests and in vivo studies to properly evaluate their action against OxS and the optimal dosage for exerting antioxidant effects.