Traumatic injuries in the central nervous system (CNS) cannot be remediated, as CNS axons cannot regrowth past the injury site or reconnect to the original target. The adult peripheral nervous system (PNS) is a well-recognized model system for studying axon regeneration for its inherent regenerative capabilities, the mechanisms of which could hopefully be applied to promote axon regeneration in the CNS. However, much of the molecular mechanisms underlying the regenerative capacity of PNS remain unknown. Considering the regrowth of axons requires various cellular functions, including but not limited, to cytoskeletal reorganization, protein and lipid synthesis, and cellular metabolism, I hypothesized that epigenetic programs, regulating a broad spectrum of cellular processes, may contribute to regulating the complex of genes. In this study, I first found the histone methyltransferase Ezh2, a key epigenetic histone remodeler is required for adult mouse PNS axon regeneration. Western-blot data indicated that membrane-associated guanylate kinase Magi3 represented one of the downstream targets epigenetically regulated by Ezh2. Based on such regulation at the molecular level, I further validated the functional interaction between Ezh2 and Magi3 in adult mouse dorsal root ganglion (DRG) and sciatic nerve (SN) PNS regeneration. Ezh2 and Magi3, either individually or in combination, were knocked down with siRNAs using in vivo SN injury model and in vitro DRG neuron culture. Briefly, I found that Ezh2 inhibition represses axon regeneration in vivo and in vitro while Magi3 inhibition could rescue the axonal regenerative suppression caused by Ezh2 inhibition, suggesting Ezh2 is necessary for intrinsic PNS axon regeneration by regulating downstream genes, including Magi3. The findings not only reveal a vital role of Ezh2 in promoting adult mammalian PNS axon regeneration but also shed light on potential therapies against various axonal pathologies.