Due to the expansion of praziquantel (PZQ) schistosome resistant strains, the detection of novel antischistosomal agents is of high seniority. Therefore, in this study, the in vitro and in vivo effects of the defatted methanolic extract of Nerium oleander leaves as well as ethyl acetate and butanol fractions against Schistosoma mansoni were evaluated. In vitro effect of extracts of N.oleander leaves have been carried against S. mansoni adult worms. The results appeared that the extracts have activity against adult worms and the mortality was highest with ethyl acetate fraction. On other hand, the Vivo antischistosomal activities of N.oleander leaves extracts on infected mice with S. mansoni was carried out compared with praziquantel. The results showed a high reduction in immature and mature eggs. Also, the number of dead eggs increased by treating infected mice with the three extracts. Beside, the antioxidant activity of infected mice was improved by treating with N.oleander leaves extracts. The defatted methanolic extract of N.oleander leaf as well as two fractions ethyl acetate and butanol, were submitted to HPLC-ESI-MS analysis. The results produce to identification of mixture phenolic acid derivatives and flavonoid glycosides in each plant extract which exhibit a respectable effect against S. mansoni infections