Tissue regeneration entails replenishing of damaged cells, appropriate cell differentiation and inclusion of regenerated cells into functioning tissues. In adult humans, the capacity of the injured spinal cord and muscle to self-repair is limited. In contrast, the amphibian larva can regenerate its tail after amputation with complete recovery of muscle, notochord and spinal cord. However, the cellular and molecular mechanisms underlying this phenomenon are still unclear. Determining these mechanisms in a model organism that exhibits this exceptional capacity to self-repair may provide the knowledge for novel therapeutic approaches to promote human tissue regeneration. One factor that has been identified as relevant for tail regeneration is electrical activity, which also plays an important role in early development of muscle and spinal cord. We hypothesize that calcium-mediated electrical activity manifests in regenerating tissues and that this activity is necessary for proper muscle and spinal cord regeneration. Calcium (Ca2+) imaging experiments show that regenerating tissues exhibit Ca2+-mediated electrical activity during the first day post-amputation. More specifically, muscle cells exhibit Ca2+ transients that depend on Ca2+ release from stores. We also find that blockade of Ca2+-mediated electrical activity impairs muscle and spinal cord regeneration. Furthermore, inhibiting Ca2+ transients in the regenerating muscle prevents the activation and proliferation of muscle satellite cells, which results in poor muscle regeneration.Our findings suggest that Ca2+-mediated electrical activity is critical for the early stages of regeneration and required for proper muscle and spinal cord regeneration. Our work contributes to understanding how Ca2+-mediated electrical activity promotes repair of injured tissues and may lead to improved therapies for tissue regeneration.