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 non-alcoholic steatohepatitis (NASH) induced experimentally by high fat diet in rats. Material and methods: Rats were divided into 5 groups: Control normal 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 pre-treated NASH group (treated with mirabegron 10 mg/kg/day orally for 12 weeks). Results: Mirabegron produced significant reduction of liver enzymes (GGT, AST, ALT), total cholesterol, triglycerides and LDL-c and significant elevation of HDL-c, Also the serum level of 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 NASH group, with the best results obtained by using the high dose of mirabegron (10 mg /kg/day).