Bombyx mori nucleopolyhedrovirus (BmNPV) is a DNA virus that infects different tissues in Bombyx mori at immature stage. Caterpillars become infected after ingesting polyhedral occlusion bodies (POB) present in contaminated mulberry leaves and spread through the body after passing the epithelium of the midgut. As this organ is responsible for digestion, most absorption of nutrients requires an intact epithelium to maintain gastrointestinal physiology. Considering the importance of this organ in the feeding of caterpillars and in the production of quality silk threads, and because it is also the first barrier faced by the BmNPV, the study analyzed details of cytopathological events in the intestinal cells as well as evaluated the action of the antioxidant systems as a response to cellular infection. For this purpose, B. mori hybrid caterpillars of fifth instar were inoculated with a suspension of 7.8 × 10⁷ POB ml^-1 and, from the first to the eighth day post-inoculation (dpi), segments of the midgut were collected and processed for light and electronic microscopy. The nuclei of columnar cells showed polyhedric occlusion bodies in the seventh dpi and fragmentation of those cells, with peritrophic matrix disorganization. Analysis of antioxidant systems shows some moments of changes of the catalase enzymes and superoxide dismutase. Analysis of the cholinergic system revealed changes only at the beginning of the infection. Thus, the article acknowledges the antioxidant system as a barrier to stop viral infection, albeit it cannot stop infection from occurring, once a coevolutionary bond is maintained between virus and host.