Background: Oral mucosal diseases manifest primarily as inflammatory conditions. These diseases affect approximately half a billion people worldwide.Objective: Novel and effective strategies for treating inflammatory diseases of the oral mucosa have great potential for improving patient outcomes, and warrant study.Methods: The impact of melatonin on inflammation was investigated using RAW264.7 macrophages and HOEC and HSC-3 oral epithelial cells.Results: Melatonin decreased macrophage-induced inflammation by acting through the melatonin receptor MTNR1A. Additionally, melatonin mitigated macrophage-induced inflammation in oral epithelial cells. Importantly, the results demonstrated that the effects of melatonin on oral epithelial inflammation were mediated through the KEAP1/Nrf2 signaling pathway.Conclusion: These findings will contribute to the development of innovative therapies for inflammatory conditions affecting the oral epithelium.