<p>Chronic pain is characterized by persistent neuronal hyperexcitability. However, the mechanisms underlying its long-term maintenance remain incompletely understood. Emerging evidence indicates that epigenetic regulation plays a critical role in shaping ion channel function, particularly potassium channels, which are key determinants of neuronal excitability. In this review, we systematically summarize how epigenetic mechanisms regulate specific potassium channel subtypes across diverse pain conditions and cell types. Unlike prior reviews on epigenetics in pain, this work focuses on the “epigenetic–potassium channel axis,” integrating multi-layered regulation with channel dysfunction across pain models. Despite these advances, key knowledge gaps remain, including the lack of selective tools to modulate channel-specific epigenetic changes, limited understanding of interactions between multiple epigenetic layers, and the absence of reliable biomarkers for monitoring epigenetic regulation in vivo. In addition, translational challenges—such as off-target effects, delivery barriers to pain-relevant neural circuits, and long-term safety concerns—must be addressed before clinical application. This review establishes a multi-layered and context-specific regulatory network linking epigenetic modifications to potassium channels dysfunction, providing new insights into chronic pain mechanisms and informing the development of targeted therapeutic strategies.</p>