UNLABELLED: Ionizing radiation has both beneficial and harmful effects on human health, prompting researchers to find ways to protect organs from its adverse impacts. Sildenafil (SIL) has gained attention in protective medicine due to its antioxidant, anti-inflammatory, and anti-apoptotic properties. AIM: This study aimed to investigate SIL's protective mechanisms against radiation-induced liver damage. METHOD: Forty adult male Wistar rats were divided into: control group, SIL group (2.5mg/kg,p.o), irradiation group (rats were exposed to single shot at a dose of 10 Gy to induce liver damage), and SIL+ irradiation group. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were evaluated. Liver samples were used to evaluate oxidative stress indicators, reduced glutathione (GSH), malondialdehyde (MDA), nitric oxide( NO), Hepatic antioxidant nuclear factor erythroid 2-related factor 2(Nrf2), and apoptoticp53 upregulated modulator of apoptosis(P53) gene expression were determined by Western blot analysis. Immunohistochemical analysis for hepatic nuclear factor-kappa B (NF-κB) and silent information regulator-1(SIRT1) were performed along with histopathological examination. RESULTS: SIL effectively diminished inflammation by reducing p-NF-κB-p65 and increasing Nrf2 and SIRT 1 expression. Additionally, SIL restrained apoptosis by reducing P53 protein expressions. Moreover, SIL significantly improved radiation-induced histopathological changes. SIGNIFICANCE: SIL preventing hepatotoxicity associated with radiation exposure.