Effective defense responses involve the entire organism. To maintain body homeostasis after tissue damage, a systemic wound response is induced in which the response of each tissue is tightly orchestrated to avoid incomplete recovery or an excessive, damaging response. Here, we provide evidence that in the systemic response to wounding, an apoptotic caspase pathway is activated downstream of reactive oxygen species in the midgut enterocytes (ECs), cells distant from the wound site, in Drosophila. We show that a caspase-pathway mutant has defects in homeostatic gut cell renewal and that inhibiting caspase activity in fly ECs results in the production of systemic lethal factors after wounding. Our results indicate that wounding remotely controls caspase activity in ECs, which activates the tissue stem cell regeneration pathway in the gut to dampen the dangerous systemic wound reaction. Recycling epithelia are sensitive to stress from the environment. Tissue stem cells respond rapidly to dying epithelia. Miura and colleagues show that cuticle wounding induced caspase activation in the gut, a tissue located distally from the wound site. Drosophila mutants for the caspase activator dark/dpf-1/HAC-1 were defective in gut cell turnover and showed increased wound-induced lethality. A lethal factor was induced in the hemolymph following wounding in dark mutants. Thus, renewal of the gut epithelia is required for overcoming an otherwise lethal response to tissue injury.