Nonalcoholic fatty liver disease (NAFLD) is a common aspect of metabolic syndrome, which includes a wide spectrum of liver damage and is closely associated with insulin resistance and lipid peroxidation. The current study aimed to evaluate the protective effect of Ilexgenin A (IA), obtained from Ilex hainanensis Merr., on NAFLD and investigate the underlying mechanisms. Sprague-Dawley rats were fed a high-fat (HF) diet for 3 weeks to induce NAFLD. They were divided into HF diet rats and HF-IA-treated rats, which were treated with IA (80 mg/kg p.o.) for 2 weeks. IA alleviated hepatic steatosis and insulin resistance and reduced plasma levels of alanine transaminase, aspartate aminotransferase, triglyceride, total cholesterol, low-density lipoprotein-cholesterol, malondialdehyde, interleukin 6, and tumor necrosis factor-α, while increasing plasma levels of high-density lipoprotein-cholesterol and superoxide dismutase (SOD). IA decreased hepatic triglycerides, total cholesterol, malondialdehyde, and restored the abnormal down-regulation of SOD. IA also decreased Cytochrome P450 2E1 expression and up-regulated peroxisome proliferator-activated receptor α (PPARα) expression in liver. These results suggested that IA had the potential to attenuate NAFLD by improving lipid metabolism, insulin resistance, inflammation, and oxidative stress, as well as adjusting the expression of Cytochrome P450 2E1 and PPARα.