Cryptosporidium is a food and water-borne enteric protozoan that infects a wide range of vertebrates, causing life-threatening complications, particularly in immunocompromised hosts. The absence of effective anti-cryptosporidial medications could be attributed to the parasite’s specific intestinal location, as well as the lack of research into the mechanism by which the protozoan impairs intestine cellular function. The present work aimed to evaluate the in vivo efficacy of zinc nanoparticles in the treatment of experimental cryptosporidiosis infection in immunosuppressed mice. Small-sized ZnO-NPs revealed better treatment efficacy than Large-sized ZnO-NPs in all studies. Nitazoxanide-treated group revealed the highest percentage reduction of the oocyst’s counts followed by the small-sized ZnO-NPs treated group. The small-sized ZnO-NPs treated mice group showed a minimal inflammatory effect in all examined treated tissues when compared to the infected non-treated group. The morphological structure of the oocysts was examined using SEM indicating variable degrees of morphological changes in the treated mice. Moreover, the levels of biochemical analyses were significantly lower in the treated group. The histopathological study revealed the significant effect of small-sized ZnO-NPs in treating cryptosporidiosis.