Many species throughout the animal kingdom naturally regenerate complex body parts following amputation. Most research in appendage regeneration has focused on identifying mechanisms that influence cell behaviors in the remaining stump tissue immediately adjacent to the injury site. Roles for activation steps that occur outside of the injury site remain largely unexplored, yet they may be critical for the regeneration process and may also shape the evolution of regeneration. Here, we discovered a role for the peripheral nervous system (PNS) in stimulating a body-wide stem cell activation response to amputation that drives limb regeneration. Notably, this systemic response is mediated by innervation at both the injury site and in distant, uninjured tissues, and by several signaling pathways, including adrenergic signaling. This work challenges the predominant conceptual framework considering the injury site alone in the regenerative response and argues instead for brain-body axis in stem cell activation as a priming step upon which molecular cues at the injury site then build tissue.