Schistosomiasis remains a major neglected tropical disease, affecting approximately 600 million individuals worldwide and accounting for nearly 500,000 deaths annually. The principal causative species — Schistosoma haematobium, S. mansoni, and S. japonicum — drive significant morbidity through hepatomegaly, splenomegaly, and progressive hepatic fibrosis. Praziquantel (PZQ) remains the cornerstone of treatment; however, its limited efficacy against immature worms and eggs, combined with concerns over emerging drug resistance, underscores the urgent need for novel therapeutic alternatives. This study investigated the anti-schistosomal potential of green-synthesized zinc oxide nanoparticles (ZnO NPs) in a murine model of S. mansoni infection, benchmarked against PZQ. ZnO NPs were fabricated using ginger extract via an eco-friendly green synthesis approach. Fifty male BALB/c mice were randomly assigned to five groups (n = 10): normal control, infected untreated control, infected treated with PZQ alone, infected treated with ZnO NPs alone, and infected treated with a PZQ–ZnO NP combination. Parasitological, histopathological, and fibrosis assessments were subsequently performed. All treatment groups demonstrated significant reductions in worm burden and tissue egg counts relative to infected untreated controls. Histopathological examination of untreated infected mice revealed extensive chronic granulomatous inflammation, concentric perioval fibrosis, fibroblast proliferation, hepatocellular necrosis, hydropic degeneration, marked collagen deposition, and portal-to-portal fibrous bridging. Treated groups, by contrast, exhibited marked hepatic improvement characterized by reduced granuloma size, diminished fibrosis, and decreased collagen deposition. Collectively, these findings indicate that green-synthesized ZnO NPs possess promising anti-schistosomal and antifibrotic properties, warranting further investigation as a potential adjunct or alternative therapeutic strategy for schistosomiasis management.