Oxidative stress is the underlying cause of various chronic diseases and can contribute to its progression. Plant-based therapeutics are effective in the prevention of various chronic diseases through the management of underlying causes. Walnuts owing to their rich phytochemistry possess antioxidative potential. In this context, the present research was designed to explore the therapeutic potential of walnut against arthritis-induced oxidative stress in rat model. Purposely, 50 Sprague Dawley rats were separated into five groups of 10 rats each. The rats were categorized as G0 (negative control), G1 (positive control), G2 (methotrexate), G3 (walnut feed), and G4 (walnut extract). Walnut feed and extract significantly reduced oxidative stress by improving the antioxidant enzymes in arthritic rats. Total oxidative stress was reduced by 41.44% and 21.52% in G3 while 52.81% and 36.76% in G4 when compared with G1 and G2 , respectively. Antioxidant enzyme levels in serum were significantly improved after the walnut-based interventions. Evidently, superoxide dismutase level improved by 74.5% in G3 and 83.40% in G4 , while catalase level increased by 51.99% in G3 and 61.34% in G4 , respectively, when compared with G1 . Liver function biomarkers, that is, ALP and AST, were decreased in G3 and G4 when compared with G1 and G2 . The histopathological examination illustrated the promising role of walnut-based interventions in conserving the structural integrity of hepatic and renal tissues. Meanwhile, gene expression analysis revealed that walnut treatments protected from oxidative damage by the downregulation of Dual-oxidases expression. Conclusively, walnut feed and extract might serve as potent antioxidant intervention with no potential side effects. PRACTICAL APPLICATIONS: The present work was aimed to evaluate the efficacy of walnut-based interventions against arthritis-induced oxidative stress. The walnut-based interventions positively modulated the antioxidant enzymes, liver, and kidney functions, while downregulating the gene associated with oxidative stress in animal model. Consequently, the current findings suggest wider applications of walnuts to avoid free radical induced damage during arthritis; however, human intervention studies may be carried out to further understand the mechanism of their bioefficacy.