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Nicotinamide (NA), a water-soluble vitamin B3, has been shown to exert cellular-protective effects against reactive oxygen species (ROS). In order to improve the cellular-protective effects of NA, we synthesized a novel compound, nicotinyl–isoleucine–valine–histidine (NA–IVH), by combining NA with jellyfish peptides’ IVH. In the present study, we examined the cellular-protective effects of the novel synthetic nicotinyl-peptide, NA–IVH. We found that NA–IVH enhances the radical scavenging activity with a robust increase of the nuclear factor (erythroid-derived 2)-like factor (Nrf2) expression in human HaCaT keratinocytes. In addition, NA–IVH protected the cells from hydrogen peroxide (H2O2)-induced cell death. Interestingly, NA–IVH exhibited an improved wound-healing effect in a high glucose condition, possibly through the regulation of reactive oxygen species (ROS). Collectively, our results imply that a novel nicotinyl-peptide, NA–IVH, has a wound-healing effect in a hyperglycemic condition, possibly by modulating excessive ROS.