Background: Depending mainly on Praziquantel (PZQ) for treatment of schistosomiasis poses a great challenge in terms of effectiveness and resistance. Nanoscale particles formed by metals as iron nanoparticles (INPs) have recently gained approval from the Food and Drug Administration for use as therapeutic agents. Therefore, INPs application as potential therapeutic agents against schistosomiasis may give promising results. Objective: The present study aimed at assessing the efficacy of INPs; iron oxide or magnetite INPs (MNPs) and zero-valent INPs (ZV-INPs) on S. mansoni using parasitological and histopathological parameters. Material and Methods: In the current study, MNPs and ZV-INPs were prepared by biogenic synthesis and were given to mice orally on the 42nd day post infection (dpi) with S. mansoni in a dose of 10 mg/kg for four consecutive doses. The therapeutic efficacy was assessed using parasitological (mortality rate, adult worm load as well as female fecundity) and histopathological parameters (tissue egg count in both liver and intestine) in comparison to untreated and PZQ treated control groups. Results: Results revealed that ZV-INPs have a significant effect in decreasing both tissue egg count and hepatic granulomata size. While the MNPs have a significant effect against the total and female worms burden, tissue egg counts, female fecundity, and number of liver granuloma. Conclusion: Herein, it was concluded that both types of INPs used in the study are potentially effective anti-schistosomal agents.