Abstract Intrahepatic cholestasis is clinical syndrome which cause either by defect in synthesis or bile acid flow, the pathophysiology of cholestasis is complicated by a number of  variables, including oxidative stress, inflammatory response, and  dysregulation of bile acid transporter . Rats, mice, and guinea pigs were utilized as experimental animals, and ANIT was administered to them in order to create a model that closely resembled intrahepatic cholestasis in human. This study examined the protective effects of papaverine, a non-narcotic opium alkaloid derived from papaver somniferum and discovered as an FXR agonist, on cholestasis in rats induced by alpha-naphthylisothiocyanate (ANIT). Rats utilized in this study divided  into 3 groups (10 rats per each groups), group I (control) or vehicle group  rat administered corn oil (1ml/kg) once daily 48 hour before sacrifice group II rats orally administered alpha-naphthylisothiocyanate (ANIT) 100mg/kg single dose 48hour before sacrifice  group III rats administered 100mg/kg papaverine orally  for 7 consecutive days and  at day 5  rat administered alpha-naphthylisothiocyanate (ANIT) The results showed that papaverine treatment decreased alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), total bilirubin, total bile acid, as well as increased antioxidant enzyme GPX and decreased MDA and inflammatory mediators tumor necrosis factor TNF- and interleukin IL1-β. In conclusion, papaverine may have a protective effect to alleviate ANIT-induced cholestasis and may be a therapeutic target to treat cholestasis.