Insects resist bacterial infection by favoring the survival and reproduction of the fittest phenotypes. The molecular mechanisms of insect immune defense have received a lot of interest, resulting in a detailed understanding of immunological pathways that are activated upon bacterial exposure. The evolution of insect resistance is mediated by alterations at the genetic level via mutation or stochastic changes in gene expression, although little is known about the contribution of epigenetic mechanisms. We established insect infection models using the lepidoptera Galleria mellonella and Manduca sexta to show that bacteria can orchestrate epigenetic changes in insects to hijack host cell signaling and immunity. Our experimental data suggest that a shift in insect resistance is associated with specific epigenetic alterations at the level of DNA methylation, histone acetylation, and non-coding microRNA expression. We highlight that these different pre-transcriptional and post-transcriptional epigenetic changes contribute to the transgenerational inherited transcriptional reprogramming of defense-related gene expression and the evolution of insect resistance to bacterial pathogens.