Honey is a rich source of antioxidant and antiseptic compounds including Maillard reaction products, vitamins, carotenoids and polyphenols. The objective of the present study was to determine the effect of digestion on the antioxidant activity of a range of honey samples including two economy brands (Tesco and Lidl), a premium Irish brand (Fainne Oir Fine Foods) and a New Zealand Manuka honey. Samples were subjected to an in-vitro digestion which simulates the human gastric and intestinal digestion system. The antioxidant activity of the honey samples before and after digestion was determined by measuring total phenol content (TPC), 2,2-diphenyl-2-picrylhydrazyl hydrate assay (DPPH) radical scavenging and ferric reducing antioxidant potential (FRAP). The ability of the samples to protect against H2O2-induced DNA damage in the Caco-2 cell line was measured by the Comet assay. The Manuka honey had the highest TPC and the Tesco honey had the highest FRAP and DPPH scavenging activity. TPC was not altered following digestion however there was a significant decrease in the FRAP values for Manuka and Tesco honey and in the DPPH radical scavenging activity for all four of the samples. The Tesco and Manuka honeys demonstrated a significant protective effect against H2O2-induced DNA damage in Caco-2 cells, following digestion. The premium brand honey samples did not demonstrate significantly higher antioxidant activity in comparison with economy brand honey.