Background: Giardiasis is the most common diarrheal disease among children and travelers and a life-threatening agent in some immunocompromised patients. Zinc is an important element in resistance to Giardia-induced intestinal damage. Objectives: evaluation of the efficacy of zinc oxide nanoparticles (ZnO-NPs) as a therapy for giardiasis and if its action as a source of zinc can give a chance to benefit from its immune stimulating and tissue protecting properties. Methodology: Therapeutic effects of ZnO-NPs were studied alone or in combination with metronidazole (MTZ) in mice experimentally infected with Giardia intestinalis. Antiparasitic efficacy, serum zinc levels, intestinal cell function, intestinal pathology, apoptosis, and local intestinal immunity were assessed. Results: Results of the present study showed that, despite the more reduction of Giardia-cysts induced by MTZ, ZnO-NPs achieved better functional, histopathological, and immunological improvement of the intestinal mucosa compared to MTZ. The best results were reached with MTZ/ZnO-NPs combination. Conclusion: ZnO-NPs killed Giardia, protected intestinal cells and helped their regeneration. These effects can be related to improved zinc levels that was also reflected on potentiation of local intestinal immunity. Besides, ZnO-NPs could decrease the incidence of apoptosis preserving properly functioning intestinal cells.