Background: Schistosoma mansoni is a trematode helminth responsible for liver fibrosis or cirrhosis. Aim of the work: In the present work natural products Thymoquinone loaded with chitosan nanoparticle (TQ/ChNP)) (TQ/ChNP) were used to determine their therapeutic effect on S. mansoni infection.   Materials and methods: A total of 40 healthy Swiss albino mice, 20-25 g in weight, procured from Theodor Bilharz Research Institute (TBRI) Imbaba, Egypt's Schistosome Biological Supply Center (SBSC).     Results: The infected mice treated with TQ/ChNP showed a significant decrease in the total worm burden. Treatment with TQ/ChNP had a highly significant effect on mature worm burden, TQ/ChNP in prophylactic and therapeutic doses significantly increased the mean number of dead ova in comparison to control. TQ/ChNP had a high decrease effect on ova count in intestinal tissue and a moderate reduction on ova count in hepatic tissue. Prophylactic dose gave a high reduction effect on ova count in intestinal tissue. As regards the size of hepatic granuloma, TQ/ChNP had the highest significant reduction on mean granuloma diameter with noticeable improvement of hepatic pathology. TQ/ChNP treated group showed observable improvement of liver pathology with mild degeneration and slight-sized fibrocellular. Conclusion: Based on the outcome of this study, TQ/ChNP proved to have potential bioactivity against S. mansoni adult stages and its potentiality in improving hepatic pathology. Efficacy of TQ/ChNP to postpone progression in chronic liver diseases must be considered as preventive medicine in patients with hepatic disorders.