The epigenome plays fundamental roles in diverse physiological processes, including the innate immune response to pathogen invasion. Dysregulation of epigenetic regulators leads to aberrant expression and activation of signaling cascades, thereby driving the development of disease. In this review, we discuss recent advances in how epigenetic regulators shape innate immune signaling networks, as well as the crosstalk between the epigenome and metabolites that have been identified as key regulatory molecules. We further highlight the critical functions of epigenetic modifiers in the pathogenesis of immune-related disorders, including sepsis and oral diseases, and summarize progress in therapeutic strategies targeting these regulatory factors.