Background: Schistosomiasis is a prevailing disease, reported globally in many countries. The classical treatment, although effective, had many disadvantages. Thus, there is a recent interest in nanoparticles [NPs] as a vehicle to increase drug effectiveness and reduce side effects.   Aim of the work: The current study was designed to evaluate the in vivo anti-schistosomal effects of praziquantel-loaded PLGA NPs compared to praziquantel [PZQ] in treatment of experimental murine Schistosomiasismansonias regards of worm burden, oogram pattern, tissue egg load, liver enzymes status [AST and ALT], cytokines changes [Interleukin 4(IL-4), Interleukin 10 (IL-10) and Interferon-gamma (IFN-γ)], Interleukin 4 [IL-4] and Interleukin 10 IFN-γ], and histopathological studies [granulomas number and diameter]. Materials and Methods: Eighty mice were classified into eight groups [10 mice each]: normal control, S.mansoni infected untreated mice [infected control], infected mice treated with unloaded PLGA NPs on the 14^th day post infection [PI], infected mice treated with unloaded PLGA NPs on the 42^nd day PI, infected mice treated with PZQ on the 14^th day PI, infected mice treated with PZQ on the 42^nd day PI, infected mice treated with PZQ-loaded PLGA NPs on the 14^th day PI and infected mice treated with PZQ-loaded PLGA NPs on the 42^nd day PI. All mice were sacrificed ten weeks PI. Results: Treated group with PZQ alone on the 42^nd day PI showed a significant reduction in total worm burden, reduction in tissue egg count, increase in serum IL-10 level, decrease in serum AST, ALT, IL-4 and IFN-γ levels and reduction in mean hepatic granulomas diameter and number when compared to infected control group. These results were improved when PZQ loaded on PLGA NPs was gevin on the 42^nd day PI showed by no detection of immature ova, a highly significant reduction in the total worm burden in comparison to infected control group. The reduction in mean hepatic granulomas diameter and number and tissue egg count in late PZQ-loaded PLGA NPs group was higher than late PZQ group. While the treated groups with PZQ alone, or loaded on PLGA NPs on the 14^th day PI and group treated with unloaded PLGA NPs on the 14^th day PI showed non-significant difference regarding total worm burden, tissue egg count, mean hepatic granulomas diameter and number and serum levels of ALT, AST, IL-4, and IL-10 compared to infected control group. Conclusion: PLGA NPs improved the anti-schistosomal effects of PZQ regarding all assessed parameters, especially a highly significant reduction in mean hepatic granulomas diameter and number by its actions through upregulation of pro-inflammatory cytokines.