Praziquantel, the main schistosomiasis chemotherapy; cannot fully counteract the infection associated morbidity including hepatic fibrosis and its sequelae. A novel therapeutic strategy is mandatory. The current study is a novel trial to assess the immunomodulatory effect of Paeoniflorin (PAE) in combination to soluble egg antigen (SEA) in schistosomiasis mansoni murine model through; parasitological, histopathological, immunohistochemical and serological studies aiming to synergistic effect that not only eliminate the parasite but also ameliorate morbidity associated to infection. Forty laboratory bred Swiss albino male CD-1 mice were used. The mice were classified into five groups (8 mice each), control healthy, control infected, PAE treated (50 mg/kg/d), SEA vaccinated (50μ protein) and combined (PAE+SEA) groups. All mice groups were sacrified 10 weeks post infection. Our results showed marked decrease in egg count/gm  stool, worm burden, granuloma diameter, tissue transforming growth factor-beta1 (TGF-β ) serum interleukin-13 (IL-13) associated with marked increase in the serum interferon-gamma (INF-γ) level in (PAE+SEA) combined group compared to all groups.