Schistosomiasis still one of the major health problems worldwide, affecting millions of people in economically challenged tropical and subtropical countries of the world. Currently the treatment of schistosomiasis relies on a single anti-parasitic drug praziquantel; however it was found it is not fully effective and the potential for development of resistant to praziquantel has justified the research for new alternative chemotherapies especially from natural sources. The current study evaluated the anti-parasitic effect of plumbagin against S. mansoni infected mice either alone or in combination with praziquantel through, parasitological parameters (worm load, oogram pattern, liver and intestine egg load) and histopathological parameters (granuloma number and diameter). Plumbagin showed a significant reduction in total worm burden (P <0.05), increase in dead eggs in oogram pattern and reduction in tissue ova count. Mean hepatic granulomas number and diameter were decreased with elevation in percentage of degenerated ova, compared to control group. Results were improved when praziquantel was used in combination with plumbagin as no male or coupled worm were detected, no immature ova and highly significant reduction in tissue egg load in liver and intestine (P < 0.001) compared to infected control group.