Schistosoma mansoni is a parasite that causes schistosomiasis, a disease that impacts millions of individuals globally. Since traditional chemical medicines are less effective against schistosomiasis because of the emergence of drug-resistant worm strains, experimenting with novel natural cures is a successful way to combat the disease. This research aimed to clarify the immune and antischistosomal effects of the bioactive compound thymoquinone from Nigella sativa loaded with chitosan nanoparticles. Five groups of mice were adjusted, with group 1 for the negative control group (non-infected and non-treated). The following 4 groups were infected with S. mansoni cercariae. Group 2 was positive control (infected and non-treated). While the mice in group 3 were infected and treated with thymoquinone. Group 4 was infected and treated by thymoquinone loaded with chitosan nanoparticles. Group 5: Infected and praziquantel-treated. Following the eighth week after infection, all mice were slaughtered. In mice treated with thymoquinone loaded with chitosan nanoparticles, the overall worm load and ova count in intestinal tissue and hepatic tissue were significantly reduced, and the mean number of dead eggs increased significantly. Comparing the serum total IgG, IgG1 and IgG2 immunoglobulin isotypes with the control group, as well as IgM antibodies against Schistosoma mansoni infection, they were considerably higher in the groups that received treatment. Therefore, it can be concluded that thymoquinone extracts from N. sativa appear to be a possible natural compound for the schistosomiasis treatment, particularly when combined with chitosan nanoparticles.