Background: The pomegranate peel extract is a rich source of natural antioxidant and antimicrobial activity. The aim of the present investigation was to evaluate the in vivo antifungal activity of the pomegranate peel extract and to compare it with nystatin against oral candidiasis in Wistar rats.Methods: Thirty-five male Wistar rats, 6 to 8 weeks old and 220 to 250 g in weight, were used for animal studies. The rats were randomly divided into 7 groups. All the rats, except the control group, were immunosuppressed with cyclosporine (40 mg/kg/d) and hydrocortisone acetate (500 µg/kg/d). Then oral candidiasis was induced via the oral administration of a suspension of Candida albicans (ATCC 10231) (2×107 cell/mL) in PBS on the palate and tongue of the animals on days 3 and 5. Treatment was initiated by using 3 different concentrations of the pomegranate peel extract (125, 250, and 500 µg/mL/kg) and nystatin 100000 U/mL/kg by gavage daily. The statistical analysis was performed using the SPSS, version 22.0. In this study, generalized estimating equations were used for data analysis to determine the effects of the pomegranate peel extract and nystatin on oral candidiasis.Results: Regardless of the concentration of the pomegranate peel extract used for the treatment of oral candidiasis, a significant improvement was seen after 15 days of treatment. All the doses of the pomegranate peel were effective against candidiasis after 15 days; the pomegranate peel extract had no adverse effects following administration in the rats.Conclusion: Our results indicated that the pomegranate peel extract is a promising approach to oral candidiasis treatment, and it may serve as a natural alternative prospect due to its potency against oral candidiasis.