By investigating the intriguing process of epigenetic changes, mainly acetylation and deacetylation of histones, we can further expand our knowledge of the development and ageing of an organism. This challenging task is made more difficult with the implication of nutritional and environmental impacts on epigenetic mechanisms. Hence, the potential use of chemicals as therapeutics that promote health and increase lifespan could bring upon a new era in natural sciences. One of the most interesting histone deacetylase inhibitors is sodium butyrate (SB). Honey bees (Apis mellifera L.) are the most frequently used model organism in ageing studies due to their extreme phenotypic plasticity in regard to lifespan and their tremendous economic importance and role in maintaining biodiversity. In this study, we showed that supplementation with SB on honey bees increased lifespan in the range of concentrations from 5 mM to 60 mM, with the highest effect at 10 mM and 20 mM. Furthermore, we showed that 10-day supplementation with those two SB concentrations up-regulated vitellogenin, histone deacetylase HDAC1 and HDAC3 isoforms (but not Sirt 1), and immune-related gene expression, as well as improved the oxidative status of honey bees by increasing antioxidative capacity, reduced glutathione (GSH) levels, protein thiol groups, and lowering lipid peroxidation. The activity of the antioxidative enzymes superoxide dismutase (SOD) and glutathione S-transferase (GST) was also affected, but no changes in catalase (CAT) activity were recorded. These findings could lead to improvements in beekeeping practice.