Background: Gamma radiation-attenuated vaccine has a very promising value in controlling schistosomiasis. The objective of this study is to investigate the effects of vaccination with gamma radiation-attenuated schistosomules regarding histopathological and immunohistochemical changes in mice model of human Schistosoma mansoni infection. Materials and Methods: The study is conducted upon 40 mice, divided into four groups of 10 each: uninfected control group A (normal control), Schistosoma mansoni infected group B (infected control), Group C subcutaneously injected with 200 Gy gamma radiation–attenuated schistosomules (vaccine control) and group D injected with the same dose of gamma radiation-attenuated schistosomules then challenged after 4 weeks by S. mansoni cercariae (vaccinated-challenged). Parts of liver tissues stained with Masson's trichrome (MT) stain for classifying the granulomas into cellular, fibrocellular or fibrous according to the amount of collagens; stained bluish green. Immunohistochemistry assay was then done on the other portion through expression of Smad2/3 protein and CD8+ in the extracellular matrix (ECM). Results: Compared to control infected group, mild histopathological changes with decrease of egg granulomas mainly cellular is detected in vaccinated-challenged group. This is accompanied with moderate immunohistochemical expression of Smad2/3 and CD8+ proteins in vaccine-control group and mild expression in vaccinated-challenged group. Conclusion: The The results indicate that vaccination with 200 Gy gamma-irradiated schistosomules could reduce histopathological and immunohistochemical changes induced due to infection which represents an effective strategy in disease control.