Objective: To explore the effect of Persea americana supplementation on inflammation, oxidative stress, and lipid profiles in ovariectomized rats fed with a high-fat diet and exposed to radiation. Methods: The control group was sham operated, while groups 2-5 were ovariectomized and fed a high-fat diet. Groups 4 and 5 were exposed to γ-radiation (1 Gy/week for 5 weeks) after ovariectomy. Groups 3 and 5 were treated with 1 mL/250 g/day of Persea americana for one month. Serum levels of estrogen, alanine aminotransferase, aspartate aminotransferase, cholesterol, triglycerides and lipoproteins were measured. Additionally, hepatic oxidative stress, inflammatory and fibrogenic markers were evaluated. Results: Persea americana treatment reduced the oxidative stress markers as well as the levels of triglyceride, total cholesterol, and low-density lipoprotein cholesterol, which in turn lowered hepatic fat accumulation. Moreover, it suppressed hepatic inflammatory mediators (interleukin-6, tumor necrosis factor-α, and C-reactive protein) and downregulated pro-fibrogenic markers (transforming growth factor-β and tissue inhibitor of metalloproteinase-1). Conclusions: Persea americana provides protection against ovariectomy, and gamma radiation-mediated hepatic inflammation not only through its antioxidant, anti-inflammatory, lipid-lowering effect but also by modulating the fibrogenic markers.