Background: Polycystic ovary syndrome (PCOS) is a common health problem in females throughout their reproductive age. Common symptoms of PCOS are hyperandrogenemia, menstrual disorders, and infertility. Metabolic disorders like insulin resistance and steatotic liver are also common. Metformin is most commonly used in the management of hyperglycemia. Erythropoietin and myoinositol were reported to improve insulin sensitivity. Objective: This study aimed to compare the potential therapeutic role of erythropoietin, myoinositol, and the widely used metformin drug against hyperinsulinemia and hepatic injury of the letrozole-induced PCOS model in rats. Materials and methods: Fifty female Wistar rats were classified equally into five groups: The control group and the PCO model group. PCO model was induced by letrozole in a dose of 0.5 mg/kg daily for 3 weeks. Then rats with PCO were administrated: erythropoietin in (EPO/PCO) group, myoinositol in (MYO/PCO) group, or metformin in (MET/PCO) group for the following 21 days. Biochemical and histological studies on the liver and pancreas were done. Immunohistochemical staining with GLUT-1 and insulin was done. Results: PCO rats developed insulin resistance with pancreatic β cell degeneration, hepatocellular injury, and upregulation of hepatic GLUT-1. Metformin, erythropoietin, and myoinositol restored β-cell mass, decreased hyperinsulinemia, and attenuated hepatocellular degeneration via the reduction of stress-induced hepatic GLUT-1. However, erythropoietin was the most effective one of them. Conclusion: Erythropoietin was more effective than metformin and myoinositol in decreasing hyperinsulinemia and attenuation of hepatocellular injury associated with the letrozole-induced model of PCOS.