Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Mirabegron is a novel, once-daily orally active, first-in-class, potent β3- adrenoreceptor (AR) agonist. Aim of the study: This work aimed at exploring the possible prophylactic effect of mirabegron on nonalcoholic steatohepatitis (NASH) induced experimentally by high fat diet in rats. Material and methods: Rats were divided into 5 groups: normal group serving as a control group, Mirabegron group, Untreated NASH group (received a high fat diet for 12 weeks), Low dose mirabegron pre-treated NASH group (treated with mirabegron 5 mg/kg/day orally for 12 weeks) and High dose mirabegron pretreated NASH group (treated with mirabegron 10 mg/kg/day orally for 12 weeks). Results: Mirabegron produced significant reduction of liver enzymes, total cholesterol, triglycerides and Low-density lipoprotein cholesterol (LDL-c) and significant elevation of highdensity lipoprotein-cholesterol (HDL-c),the serum level of glycosylated hemoglobin (HbA1c), fasting glucose and insulin levels were significantly decreased with significant improvement of insulin sensitivity observed by lowering of insulin resistance index (HOMA-IR), serum adiponectin level also showed significant elevation. These results were supported by marked improvement of liver histopathology compared to non-treated group, with the best results obtained by using the high dose of mirabegron. Conclusions: These data suggest that mirabegron may have a potential usefulness in the prevention of NASH as regard to liver enzymes, lipid profile, serum HbA1c, fasting insulin and blood glucose, insulin resistance index, and serum adiponectin levels with improvement of liver histopathological changes.