The chemical drugs are safe and effective being the main tool in controlling schistosomiasis. Referring to the possibility of appearance of drug resistant parasites especially with retreatment regimens in endemic areas, search for new schistosomicidal is essential. Nigella sativa has been extensively studied for its biological activities and therapeutic potentials and shown to possess wide spectrum of activities including antihelminthic and antiprotozoal activities. The present report aimed to investigate the prophylactic and therapeutic effect of Nigella sativa oil in treatment of Schistosoma mansoni. Nigella sativa oil was administrated orally to S. mansoni infected mice in two different doses, a prophylactic dose (1.14g/kg) every day for 2 weeks before infection and a therapeutic dose (1.14g/kg) daily for 4 weeks starting from 2nd day post infection aiming to investigate its potential therapeutic role. Therapeutic treatment with Nigella sativa oil had a high significant effect on mature worm burden, as the reduction percentage was (57.5%). Nigella sativa oil in prophylactic and therapeutic doses significantly increased the mean number of dead ova (14.75±6.5) and (21.43±3.64) respectively in comparison to control (5.25±1.71). Nigella sativa oil therapeutic dose had a high reduction effect on ova count in intestinal tissue (81.45%) and a moderate reduction on ova count in hepatic tissue (57.86%). Prophylactic dose gave a high reduction effect (78.76%) on ova count in intestinal tissue. As regard the size of hepatic granuloma, Nigella sativa oil treated group had the highest significant reduction on mean granuloma diameter; the reduction was 26.69% with marked improvement of hepatic pathology. N. sativa oil treated group showed obvious improvement of liver pathology with mild hydrobic degeneration and small sized fibrocellular granuloma accompanied by multiple malformations in both S. mansoni adult worms. These results showed that N. sativa oil has remarkable effect on mature S. mansoni which could be helpful for potentiating Praziquantel effect and thus reducing development of resistance.