After mid-gastric bisection, Hydra regenerates a head from the lower half and a basal disc from the upper one. What signals elicit two distinct regenerative responses in bisected Hydra remains unknown. A mathematical modeling approach based on quantitative data linked to MAPK activation and injury-induced cell death predicts an immediate release of a locally restricted short-lived signal in apical-regenerating tips. We found that Reactive oxygen species (ROS) fulfill this role as evidenced by the injury-induced production of hydrogen peroxide (H₂O₂), three-fold higher in apical-regenerating tips than in basal ones. By contrast, mitochondrial superoxide (mtO₂ ^.- ) is similarly produced on each side of the cut, playing a positive role on wound healing as mtO₂ ^.- scavenging delays healing whereas knocking-down Super Oxide Dismutase (SOD) leads to mtO ₂ ^.- accumulation and acceleration of wound-healing. In intact Hydra , the ROS-processing enzyme activities are inversely graded along the body column, basal-to-apical for SOD and apical-to-basal for catalase, explaining the asymmetrical levels of H₂O₂ after bisection. High H₂O₂ levels trigger injury-induced cell death via paracrine signaling in apical-regenerating tips, where NOX4 and CYBB enzymes amplify them. Hence, the asymmetrical regulation of H₂O₂ levels immediately after amputation is crucial to activate two distinct regenerative responses in Hydra .