Hepatic sinusoidal obstructive syndrome (SOS) is a rare drug-induced fibrous occlusive hepatic entity. Up to now, there is no perfect therapy to avoid SOS, therefore, new curative options are clearly needed. The current research pointed to explore the probable protective effect of sildenafil against monocrotaline (MCT)-induced SOS, and to further identify the underlying mechanisms. Sildenafil was given to rats for 7 days orally (5 mg/kg/day). In the fourth day animals fasted, and given 90mg/kg MCT. Twenty-four hours after last dose of sildenafil administration, liver tissue and blood were collected to evaluate SOS. Results revealed that sildenafil amended oxidative stress in liver tissue as indicated by the significant increase in hepatic GSH level. Furthermore, sildenafil treatment significantly decreased the expression of liver sinusoidal endothelial cell injury markers (hyaluronic acid (HA), Vascular Cell Adhesion Molecule-1 (VCAM-1), and plasminogen activator inhibitor‐1(PAI-1), platelet aggregation markers (CD34, CD41 and P-selectin), as well as serum transaminases and hepatic caspase-3 activities. Additionally, macroscopic and histopathological examination of liver tissue augmented our biochemical findings. In conclusion, sildenafil markedly reversed the complicated and multifactorial pathophysiological state of SOS induced by MCT through its cytoprotective, thromboresistance effect on hepatic sinusoidal endothelial cells. Thereby, sildenafil proves to be a promising new therapeutic agent for SOS.