Abstract: Oral mucositis (OM) is a common complication in head and neck squamous cell carcinoma (HNSCC) treatment, and no effective treatment strategies are currently available. The incidence of radiotherapy-induced OM (RIOM) and chemotherapy-induced OM (CIOM) in patients with head and neck cancer incidence rate is as high as 90%. The current treatment methods, including nutritional support, pain control, and prevention of secondary infections, are mainly focused on alleviating symptoms and preventing complications. The oral microbiota play a crucial role in maintaining the functional homeostasis of the oral cavity, regulating the microenvironment, and influencing the progression of oral diseases. The interaction between microorganisms and the host regulates the dynamics of the oral microbiome. Although the development and presence of OM is generally related to changes in the oral microbiota and the type of host immune response in the oral cavity, specific mechanisms underlying mutual microorganism-immune cell regulation, adverse reactions resulting from imbalanced microorganisms-immunity interaction, and their key roles in OM development have not been fully elucidated. This study aimed to elucidate the mechanisms underlying oral microbiota-host immune system interaction, focusing on the epigenetics regulation of OM that contributes to its pathophysiological mechanisms in HNSCC. Elucidating these mechanisms may reveal potential targets for novel biological therapy development.