Background: Celastrol, a pentacyclic triterpenoid active component isolated from the root bark of the traditional medicinal plant Tripterygium wilfordii, displays significant anti-inflammatory, antioxidant, and immunomodulatory properties. However, its clinical application remains limited due to inadequate bioavailability. Methods: Regarding these issues, we innovatively developed a novel peanut cultivar (cel-peanut) enriched with celastrol through distant hybridization combined with metabolomics screening. Guided by the research concept of “natural anti-inflammatory diets for metabolic disease management”, we established a high-fat diet-induced ApoE^−/− atherosclerotic mouse model to systematically evaluate the anti-atherosclerosis effects and mechanisms of cel-peanut. Results: Our results revealed that cel-peanut significantly reduced serum levels of triglycerides (TGs) and increased high-density lipoprotein cholesterol (HDL-C). Concurrently, cel-peanut markedly decreased the atherosclerotic lesion area and enhanced collagen content within plaques. Mechanistic investigations demonstrated that cel-peanut reduced serum malondialdehyde (MDA) levels and suppressed the concentration of pro-inflammatory cytokine IL-6 in atherosclerotic lesions. Furthermore, cel-peanut promoted intestinal health by modulating the composition and functionality of gut microbiota, thereby attenuating atherosclerosis progression. Conclusions: Overall, these findings indicate that cel-peanut exerts therapeutic effects against atherosclerosis through its anti-inflammatory, antioxidant, and gut microbiota-modulating properties. This study proposes a novel nutritional intervention strategy for atherosclerosis and provides a promising adjuvant strategy for clinical atherosclerosis treatment.