This study was performed to assess the use of chitosan (Cs) and zinc oxide nanocomposites ZnO NCP with full and half dose mebendazole (MBZ) during the muscular phases of T. spiralis infection. Sixty Swiss Albino male mice were divided into six groups: G1 (negative control), G2 (positive control), G3 (MBZ at 200 mg/kg/day), G4 (Cs@MBZ NCP at 400 mg/kg/day), G5 (Cs@MBZ400.ZnO NCP), and G6 (Cs@MBZ200.ZnO NCP). Mice were infected orally with 200 T. spiralis larvae and received treatments starting on day 35 post-infection for five consecutive days. Treatment outcomes were evaluated by counting total muscular larvae, conducting blood biochemical measurements, and performing histopathological examinations of the liver and hip joint muscles. ELISA was used to measure serum levels of transforming growth factor-beta1 (TGF-β1), tumor necrosis factor-alpha (TNF-α), and vascular endothelial growth factor (VEGF). Results indicated that both Cs@MBZ400.ZnO NCP and Cs@MBZ200.ZnO NCP groups exhibited significant reductions in muscular larval counts (96.4% and 96.1%, respectively). Treated mice also showed reduced AST and ALT levels, increased total protein and albumin, and decreased globulin levels compared to positive controls. Cytokines levels of TNF-α, TGF-β1, and VEGF were lower in treated groups. Histopathological examination revealed that Cs@MBZ400.ZnO and Cs@MBZ200.ZnO NCP restored up to 90% of normal tissue architecture. In conclusion, chitosan and zinc oxide nanocomposites enhanced the therapeutic ability of mebendazole against T. spiralis muscular stage as these nanocomposites had the highest effect on reducing parasite burden, improving blood biochemical, decreasing cytokines levels and restoring normal histological architecture.