This research evaluates the value of loading Nigella sativa on chitosan nanoparticles (ChNPs) in the treatment of Schistosoma mansoni infection compared to praziquantel. Chitosan has efficient oral administrative capability to penetrate mucosal surface being mucoadhesive and non-toxic, as well as combination with NPs add characters of controlled release and safe serum levels. The study was done on 40 S. mansoni infected male mice which were divided into 4 groups: positive control group (infected, non treated), group treated with N. sativa only (NS), group treated with N. sativa loaded chitosan NPs (NC) and group treated with combined praziquantel and N. sativa loaded chitosan nanoparticles (NCP). Results showed decreased worm burden in NC and NCP groups concerning the control and NS groups while significant decrease occurred in oogram pattern and tissue egg loads reached reduction percentages more than 90% in NC and NCP groups. On the level of granuloma diameter reduction, it was 46.3% in NC and 41.3% in NCP group while granuloma number was reduced by 50.9% in NC and reduced by 32% in NCP group revealing the apparent role of ChNPs in improvement of bilharzial hepatic changes. Thus, ChNPs improved the effects of N. sativa in therapy of murine schistosomal infection by enhancing the effects of praziquantel and reducing the resistance to it. This can be considered as a new strategy using ChNPs as anti-schistosomal drug carrier in mice models.