The present study is designed to evaluate the therapeutic effect of Crocus sativus(saffron) aqueous extract (CSE) alone or in combination with praziquantel on Schistosoma mansoni infected mice. Parasitological, immunological, pathological and immunohistochemical parameters and surface topography of worms were determined. Treatment of S. mansoni infected mice with saffron or PZQ revealed a significant reduction in worm burden, hepatic and intestinal ova count with a decline in granuloma diameter. There was an increase in total IgG and IL-10 blood levels after treatment with PZQ and/or CSE. Superoxide dismutase (SOD) and catalase levels were improved in infected mice treated with CSE in comparison with infected mice. Male worm surface ultrastructure examination showed a swelling, rupture of numerous tubercles with marked decrease in spines and severe peeling of tegumental dorsal surfaces after treatment with saffron. In conclusion, the administration of aqueous extract of Crocus sativus is effective treatment for S. mansoni infection.