Schistosomiasis represents a major health challenge and problem in many tropical and subtropical countries despite continuing control efforts. The global strategy for the control of schistosomiasis is the repeated, large-scale administration of the antischistosomal drug praziquantel (PZQ) to at risk populations but PZQ therapeutic profile is deficient, so a variety of highly effective drugs now exist for the treatment of schistosomiasis. Recently Plumbagin (PL) has been identified as a potent anti-schistosomal and anti-fibrotic drug that may suppress liver fibrosis induced by Schistosoma mansoni (S. mansoni). This study evaluated the anti-parasitic effect of PL against S. mansoni infected mice by, using parasitological parameters (worm load, liver egg load), histopathological parameters (granuloma number, diameter, type and state of egg) and immunohistochemistry (CD14, STAT3 and Collagen1). Plumbagin showed a significant reduction in total worm burden, tissue egg load, mean hepatic granulomas number and diameter with elevation in percentage of degenerated ova in infected treated group, in comparison to the control infected group. Also, attenuation of collagen deposition in liver was observed as the abnormal expressions of collagen markers were lowered in the presence of PL. The best results were obtained when PL was combined with PZQ. Therefore, it could be concluded that Plumbagin showed a promising anti-schistosomal agent with anti-fibrotic properties, and this make it one of the new potential targets in chemotherapy against schistosomiasis.