Spinal cord injury that results in severe neurological disability is often incurable. The poor clinical outcome of spinal cord injury is mainly caused by the failure to reconstruct the injured neural circuits. Several in-trinsic and extrinsic determinants contribute to this inability to reconnect. Epigenetic regulation acts as the driving force for multiple pathological and physiological processes in the central nervous system by modu-lating the expression of certain critical genes. Recent studies have demonstrated that post-SCI alteration of epigenetic landmarks is strongly associated with axon regeneration, glial activation and neurogenesis. These findings not only establish a theoretical foundation for further exploration of spinal cord injury, but also provide new avenues for the clinical treatment of spinal cord injury. This review focuses on the epigenetic regulation in axon regeneration and secondary spinal cord injury. Together, these discoveries are a selection of epigenetic-based prognosis biomarkers and attractive therapeutic targets in the treatment of spinal cord injury.