Background: Polycystic ovary syndrome (PCOS) is characterized by polycystic ovarian follicle morphology, ovulatory dysfunction, hyperandrogenism and insulin resistance. Spexin has a role in satiety control, lipid and glucose metabolism. Metformin is an insulin sensitizing agent that has some hepato-protective functions. Aim: This study aimed to declare and compare the effect of spexin and metformin treatment on ovarian and liver function changes in letrozole-induced PCOS in rats and the possible mechanisms involved. Methods: Thirty-two adult female Wistar albino rats divided into control, polycystic ovary syndrome (PCOS), PCOS metformin-treated, and PCOS spexin-treated groups. In PCOS groups, rats were given oral letrozole 0.5 mg/kg dissolved in 0.9% NaCl once daily along the study. In PCOS metformin-treated group, rats were treated with metformin hydrochloride orally (300 mg/kg/day) for the last 4 weeks. In PCOS spexin-treated group, rats were treated with spexin i.p. 35 μg/kg/day, dissolved in normal saline for the last 4 weeks. Results: In PCOS group, there was a significant increase in; BMI, relative ovarian weight, HOMA-IR, serum (LH, FSH, testosterone, insulin, glucose, TC, TG, LDL, ALT, AST, alkaline phosphatase, total & direct bilirubin) and hepatic (MDA, NO & TNF-), with a significant decrease in; serum [estradiol, progesterone, HDL, albumin and spexin] and hepatic GPX, when compared with the control group. Histopathological results showed ovaries of PCOS marked expression of caspase-3 and P53 and decreased KI67 expression of granulosa and theca cells. Vacuolated hepatocytes, dilated and congested portal vein and positive reaction of immunostaining with αSMA, caspase and TNFα. Treatment of PCOS rats with either metformin or spexin reversed these changes significantly. Conclusion: Spexin serum level could be used as a metabolic biomarker for polycystic ovary syndrome. Also, treatment with either metformin or spexin ameliorated ovarian and hepatic dysfunctions in rat model of PCOS through their insulin sensitizing, anti-oxidant and anti-inflammatory effects.