Schistosomiasis is a fatal disease that has a negative impact on health and economics. Praziquantel (PZQ) is the drug of choice for schistosomiasis treatment, but it has no prophylactic effect; therefore, vaccination is an essential requirement in schistosomiasis control. This work was carried out to investigate the possible effect of DNA vaccination against Schistosoma mansoni infection using recombinant S. mansoni fatty acid binding protein (rsmFABP). The smFABP gene was cloned into the eukaryotic expression vector pcDNAI/Amp in order to obtain an smFABP-pcDNAI recombinant plasmid (DNA vaccine) and was used for the intramuscular DNA vaccination of out-bread Swiss albino mice prior to infection with S. mansoni cercariae. Infected groups, either DNA vaccinated or unvaccinated, were treated with PZQ at week 6 post-infection. After 8 weeks post-infection, all mouse groups were sacrificed and parasitological, immunological and histopathological parameters were studied. DNA vaccinated mice showed a high titer of anti-smFABP-IgG antibodies and acquired significant protection (74.2%, p < 0.01) against S. mansoni infection, with a reduction in ova and granuloma counts. DNA vaccinated and PZQ treated animals had higher titers of anti-smFABP-IgG antibodies and decreased (87%, P < 0.001) parenchymal granulomas compared to the DNA vaccinated PZQ untreated group. Infected mice, either non DNA vaccinated or vaccinated, had very high collagen content and fibrous granulomas (74%) compared to the PZQ treated group (10.3% fibrous granuloma) and PZQ treated + DNA vaccinated group (0% fibrous granuloma). In conclusion, DNA vaccination had protective and anti-pathological effects in naive mice and greatly improved the pathological status in PZQ-treated animals, suggesting an immunological and pathological modulating effect of PZQ treatment.