Trichinellosis is a worldwide zoonotic disease affecting a wide range of mammals, including humans. It has intestinal and muscular phases. The current work was done to experimentally evaluate the efficacy of zinc oxide nanoparticles (ZnO NPs) and their combination with albendazole on intestinal and muscular stages of Trichinella spiralis (T. spiralis) infection. We had five main groups of mice: Group 1, non-infected control; Group 2, infected control; Group 3, infected and treated with albendazole; Group 4, infected and treated with ZnO NPs; and Group 5, infected and treated with albendazole and ZnO NPs. Each group was divided into two subgroups (A for the intestinal phase and B for the muscular phase). Drug effects were evaluated by parasitological, histopathological, and biochemical studies, including oxidant/antioxidant analysis and vascular endothelial growth factor (VEGF) gene expression in muscle tissue by quantitative real-time PCR. ZnO NPs resulted in a significant reduction of both intestinal and muscular phases of T. spiralis. Their combination with albendazole resulted in the complete eradication of adult worms and the maximum reduction of larval deposition in muscle tissue. Additionally, the treatment showed improvement in T. spiralis-induced pathological changes and oxidative stress status. Moreover, a significant decrease in VEGF gene expression was detected in the treated groups when compared with the infected control. In conclusion, ZnO NPs presented an antihelminthic effect against both adult and larval stages of T. spiralis. In addition, it enhanced antioxidant status and suppressed angiogenesis in muscle.