Simple SummaryHoney bees are key pollinators in agricultural crops. Today, honey bee colonies in decline are a global concern as a result of various stressors, including pesticides, pathogens, honey bee health, and parasites. A healthy honey bee colony refers to colonies that are not exposed to biotic and abiotic stressors. In this study, we examine how thiamethoxam (pesticide) and deformed wing virus type A (DWV-A) interact in effects on honey bee health. The results revealed that the honey bees were infected with DWV-A and were additionally exposed to thiamethoxam, showing effects that increased the mortality rate, and crippled wings in newly emerged adult honey bees. Moreover, the exposure to thiamethoxam and DWV-A injection resulted in induced expression of immune genes (hymenoptaecin gene) while downregulation of two apoptosis genes (caspase8-like, caspase9-like genes). The impact interaction of pesticide and DWV-A have on the expression of apoptosis genes can directly affect viral susceptibility in the honey bee host.Honey bees are economically important insects for crop pollination. They play a significant role as pollinators of wild plants and agricultural crops and produce economical products, such as honey, royal jelly, wax, pollen, propolis, and venom. Despite their ecological and economical importance, the global honey bee population is in decline due to factors including pathogens, parasites, intensive agriculture, and pesticides. Moreover, these factors may be interlinked and exacerbate the loss of honey bees. This study aimed to investigate the interaction between a pesticide, thiamethoxam, and deformed wing virus type A (DWV-A) to honey bees and the effects on survival rate, wing characteristics, and expression of immune and apoptosis genes in Apis mellifera. We described the potential interaction between thiamethoxam and DWV-A on honey bee wing characteristics, DWV-A loads, and the expressions of immune (defensin, abaecin, and hymenoptaecin) and apoptosis genes (buffy, apaf1, caspase3-like, caspase8-like, and caspase9-like). Honey bee larvae were fed with three different thiamethoxam doses (0.001, 1.4, and 14.3 ng/µL of the diet). Then, thiamethoxam-treated white-eyed pupae were injected with 107 copy numbers/honey bee of the DWV-A genome. The interaction between thiamethoxam and DWV-A caused a high mortality rate, crippled wings in newly emerged adult honey bees (100%), and resulted in induced expression of hymenoptaecin gene compared to the control group, while downregulation of caspase8-like, caspase9-like genes compared to the DWV injection group. Therefore, the potential interaction between thiamethoxam and DWV-A might have a deleterious effect on honey bee lifespan. The results from this study could be used as a tool to combat DWV-A infection and mitigate pesticide usage to alleviate the decrease in the honey bee population.