Among biopesticides, Bacillus thuringiensis (Bt) is the most widely used in agriculture for the control of insect pests and vectors. Bt is a Gram-positive endospore-forming bacterium that produces a wide range of toxins with specific biological targets. Bt strains differ by the production of diverse -endotoxins cocktails, which define potential target hosts. These findings have long motivated the isolation and characterization of new Bt strains for the use as biocontrol agents. However, the inadvertent effects of these bacteria on non-target organisms remain largely unexplored. In this study, we have developed an oral infection model to investigate the putative effects of different Bt strains on Drosophila melanogaster as a non-target host. Taking advantage of the powerful molecular and genetic tools of this model organism, we explore the epithelial reactions triggered upon the ingestion of Bt spores and the relative contribution of epithelial defenses in the fight against the infections. Our data emphasize a toxin-dependent epithelial induced response and highlights the major contribution of the epithelial arm of defense in the control of Bt oral infections.