This study assessed the effectiveness of an aqueous extract of Moringa Oleifera Lam. leaves (MOL) alone or in combination with praziquantel (PZQ) drug targeting–infected mice with Schistosoma mansoni-induced liver and spleen damage. Mice were divided into eight groups control mice group treated orally with saline. PZQ group: non-infected mice treated orally with 300 mg/kg bwt PZQ three consecutive days. MOL group: non-infected mice treated orally with 150 mg/kg bwt MOL extract for 15 days. PZQ/ MOL group: non-infected mice treated orally with 300 mg/kg bwt PZQ for three consecutive days and 150 mg/kg bwt MOL extract for 15 days. IF group: infected mice with 100 cercariae/mouse of the Egyptian strain of S. mansoni. IF/PZQ group infected mice with S. mansoni cercariae and treated orally with 300 mg/kg bwt PZQ for three consecutive days. IF/MOL group: infected mice with S. mansoni cercariae treated orally with 150 mg/kg bwt MOL extract for 15 days. IF/PZQ +MOL group: infected mice with S. mansoni cercariae treated orally with 300 mg/kg bwt PZQ for three consecutive days and 150 mg/kg bwt MOL extract for 15 days. Blood, liver, spleen, worm, and eggs were collected at the end of the experimental period. Treatment of infected mice with MOL and PZQ together significantly reduced the number of ova/g tissue and eliminated the parasites. In addition, the liver and spleen of infected mice showed less histopathological alteration and immunohistochemical expression of nuclear factor kappa β (NF-Kβ). We can conclude that MOL extract combined with PZ has a curative effect on S. mansoni infection and helped to lessen its pathological effects.