Honey bee colonies in the USA have suffered from increased die-off in the last few years with a complex set of interacting stresses playing a key role. With changing climate, an increase in the frequency of severe weather events, such as heat waves, is anticipated. Understanding how these changes may contribute to stress in honey bees is crucial. Individual honey bees appear to have a high capacity to endure thermal stress. One reason for this high-level endurance is likely their robust heat shock response (HSR), which contributes to thermotolerance at the cellular level. However, less is known about other mechanisms of thermotolerance, especially those operating at the tissue level. To elucidate other determinants of resilience in this species, we used thermal stress coupled with RNAseq and identified broad transcriptional remodeling of a number of key signaling pathways in the honey bee, including those pathways known to be involved in digestive tract regeneration in the fruit fly such as the Hippo and JAK/STAT pathways. We also observed cell death and shedding of epithelial cells, which likely leads to induction of this regenerative transcriptional program. We found that thermal stress affects many of these pathways in other tissues, suggesting a shared program of damage response. This study provides important foundational characterization of the tissue damage response program in this key pollinating species. In addition, our data suggest that a robust regeneration program may also be a critical contributor to thermotolerance at the tissue level, a possibility which warrants further exploration in this and other species.