ABSTRACT Background: Heterophyiasis is one of the food-borne trematode infections, caused by the intestinal fluke Heterophyes heterophyes. The exact role of nitric oxide (NO) in the immune response against the majority of parasites remains controversial. It proved protective against a wide range of protozoan and helminthic parasites. Nevertheless, its role in intestinal heterophyiasis is yet to be explored. Objectives: The study aims to explore the possible roles of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS) in experimental intestinal heterophyiasis. Material and Methods: The experimental study design included infection of male puppies with H. heterophyes encysted metacercariae (EMC), followed by treatment with aminoguanidine (AG) and 7-nitroindazole (7-NI) drugs, as selective inhibitors of iNOS and nNOS, respectively. Controls included non-infected and infected untreated puppies. Intestinal tissue sections from all puppies were stained for histopathological and immunohistochemical (IHC) assessments. Results: Different intensities of iNOS and nNOS isoenzymes were observed in intestinal sections. The study showed the highest concentration of iNOS isoenzyme in the infected-7-NI treated group. The control noninfected puppies exhibited the highest levels of nNOS expression, with statistical significance (P<0.05). The study also showed that AG significantly reduced the degree of inflammatory cellular infiltrations. Additionally, the over-production of NO worsened the degree of intestinal apoptotic changes. Conclusion: Results obtained in the study suggested that inhibition of iNOS, to some extent, improved intestinal architecture, while inhibition of nNOS failed to eliminate experimental intestinal heterophyiasis.