Although the current treatment of schistosomiasis relies largely on praziquantel (PZQ), it has not significantly reduced the overall number of disease cases, perhaps due to inevitable resistance to PZQ. Previous studies showed that radiation-attenuated vaccine gives protection levels for Schistosoma mansoni in host various species. In the present study, we evaluated the effect of various vaccination strategies in C57BL/6 mice, including single or multiple vaccination strategy, subcurative dose (20 mg/kg) of PZQ, and a combination of single vaccination with subcurative dose of PZQ. Groups of five mice were sacrificed postinfection in 42 days and schistosomes were collected by perfusion and examined by scanning electron microscopy. Treatment either with subcurative dose of PZQ or with a single vaccination of attenuated cercariae (500 per mouse), caused significant reduction in total worm burden, hepatic and intestinal ova counts 43.03%, 73.2%, 59.5% and 37.97%, 52.02%, 26.3%, respectively. Furthermore, tegumental changes were observed, including severe swelling, fusion of tegumental folds, vesicle formation, and loss or shortening of the spines on the tubercles. However, multiple vaccination strategy resulted in much higher reduction in total worm burden, hepatic and intestinal ova count. However, multiple vaccination strategy resulted in high reduction of worm burden, hepatic and intestinal ova counts 72.5%, 90.7%, 65.79%, respectively, and further causing swollen, disruption of tubercles teguments and erosion, extensive peeling, fusion of tegumental folds. Our findings suggest that multiple vaccination strategy is the most effective strategy to clear schistosomal infection, indicating its potential in guiding the design of appropriate therapeutic strategy against schistosomes.