Background: Complementary remedies such as the Chinese herb ‘Sheng Ma’ (Black cohosh; Actaea racemosa ‘AR’) are being sought to overcome the shortcomings of conventional hormonal and surgical therapies developed for treatment of polycystic ovary syndrome (PCOS). However, the AR hepatotoxicity urges a cautionary warning to be labeled on its products as recommended by the United States Pharmacopeia, where four out of seven hepatotoxic cases in Sweden were possibly associated with black cohosh products.Methods: We investigated the effects, safety, and molecular targets of black cohosh ethanolic extract and/or vitamin C on ovarian functionality and oxidative response in hyperandrogenism-induced PCOS rats. A well-established rat model using oral letrozole, daily, for 21 days was employed then rats received the AR extract with and without vitamin C for 28 days. The hormonal evaluation, antioxidant status, histopathological examination, immunohistochemical analysis, cell proliferation, and the expression ratio of the aromatase (Cyp19α1) gene were evaluated. Additionally, a holistic profiling of AR arsenal of secondary metabolites was performed using ultra high-performance liquid chromatography (UHPLC) coupled with quadrupole high resolution time of flight mass spectrometry (QTOF-MS).Results: Beneficial effects were exerted by AR in PCOS rats via the improved antioxidant status, hormonal profile, lipid profile, glucose level, liver functions, and the induced Ki-67 expression in the granulosa, theca cell layers and interstitial stromal cells. Notably, the combination of AR with vitamin C was not only more effective in reversing the dysregulated levels of testosterone, luteinizing hormone, and mRNA level of Cyp19α1 gene in the PCOS rat, but also safer. The combination regulated both ovarian and hepatic MDA and GSH levels with histological improvement observed in the liver and ovaries. In addition, the untargeted metabolomic profiling enabled the identification of 61 metabolites allocated in five major chemical classes.Conclusion: This study demonstrated the benefit of the combination between AR and vitamin C in mitigating the reproductive and metabolic disorders of PCOS with the elimination of AR hepatotoxic risk.