--- - |2 Summary Liver fibrosis is a health challenge requiring alternative therapeutic approaches. Cilostazol is a selective phosphodiesterase‐3 inhibitor and possesses antioxidant, anti‐inflammatory and antifibrotic properties. Sirtuin 1 (SIRT1) is a member of the silent information regulator 2 family. Cilostazol upregulates SIRT1 expression. Cilostazol protects against the cholestatic liver insults caused by bile duct obstruction. Involvement of SIRT1 pathway in this protective effect has not been studied yet. So, we hypothesized that SIRT1 signaling may have a role in cilostazol protective effects against bile duct ligation‐induced liver damages. Rats were subjected to common bile duct ligation then treated with cilostazol (9 mg/kg or 27 mg/kg) in the presence or absence of specific SIRT1 inhibitor EX527. Cilostazol improved liver function, reduced inflammation, enhanced antioxidant status, ameliorated cholestatic liver injury and upregulated hepatic SIRT1. However, these protective effects were abrogated by EX527, suggesting that SIRT1 signaling may have a role in these effects. In conclusion, cilostazol in a dose‐dependent way produced hepatoprotective effects via anti‐inflammatory, antioxidant, antifibrotic effects which were mediated, in part, through SIRT1 upregulation. - 'Clinical and Experimental Pharmacology and Physiology, Volume 45, Issue 12, Page 1341-1350, December 2018. '