Chemotherapy is the most widely advocated method of Schistosome control. However, repeated chemotherapy leads to the emergence of drug-resistant Schistosoma strains. Therefore, efforts to find alternative drugs, especially those of natural origin, have risen globally. Nanoparticles (NPs) have received special interest as efficient drug delivery systems. This work aimed to investigate the anti-schistosomal potential of Zingiber officinale (ginger, Zingiberaceae)-loaded chitosan nanoparticles (GCsNPs) on Schistosoma mansoni experimentally infected mice that were exposed to 80 ± 10 cercariae/mouse. The study groups are: (G1) negative control; (G2) positive control; (G3) praziquantel in a dose of 500 mg/kg/day for two consecutive days; (G4) ginger in a dose of 500 mg/kg treated; (G5) chitosan nanoparticles in a dose 3 mg/kg (G6) GCsNPs in a dose 250 mg/kg; and (G7) GCsNPs in a dose 500 mg/kg. The anti-schistosome potential was assessed using histopathological scanning electron microscopically and immunological parameters. The results showed that there was a significant decrease in cellular granuloma count (p < 0.05) and granuloma diameter (p < 0.001) in all infected treated mice groups, in comparison to the infected non-treated group with the highest reduction in both G3 and G7. SEM of S. mansoni adult worm recovered from G3 showed mild edema of oral and ventral suckers with some peeling and blebs around them, while that recovered from G7 showed abnormal oedematous oral and retracted ventral sucker, edema of the tegument, rupture of many tubercles with vacuolation and complete loss of spines. All infected treated mice groups, in comparison to positive control G2, showed a significant reduction in IL-4, IL-10, and TNF-α levels (p-value < 0.001), especially groups G6 and G7 (p-value < 0.05); both G6 and G7 values were nearer to the normal that indicated recovery of the liver tissue.