The aim of this study was to evaluate the effect of Santolina chamaecyparissus ethanol (SCE) and aqueous (SCA) extracts against paracetamol-induced liver damage in male rats. In this study, SCA and SCE (30, 150 or 300 mg/kg body weight) was administered daily for 7 days in experimental animals. Liver injury was induced chemically, by paracetamol administration (3 g/kg b.w.). The hepatoprotective activity was assessed using biochemical parameters like alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) and histopathological study. Furthermore, polyphenols and flavonoids content was determined by colorimetric methods. Obtained results demonstrated that the treatment with SCA and SCE significantly (P<0.01) prevented chemically induced increase in serum levels of hepatic enzymes. The inhibitory effect was close to that of silymarin 100 mg/kg, used as standard. Histopathological examination showed that SCE and SCA protected against hepatocytic necrosis. Phytochemical analysis revealed that SCE and SCA are rich in polyphenols and flavonoids. The present study revealed that S. chamaecyparissus exhibits hepatoprotective activity and it can constitute a promising natural source to develop novel therapeutic drugs for treating liver disorders.