Metazoans have evolved efficient mechanisms for epidermal repair and survival upon injury. Several cellular responses and key signaling molecules involved in wound healing have been identified in Drosophila but the coordination of cytoskeletal rearrangements and the activation of gene expression during barrier repair is poorly understood. The Ret-like, receptor tyrosine kinase Stitcher (Stit) regulates both re-epithelialization and transcriptional activation by Grainy head (Grh) to induce extracellular barrier restoration. Here, we describe the immediate down-stream effectors of Stit signaling in vivo. Drk (downstream of receptor kinase) and Src-family tyrosine kinases bind to the same docking site in the Stit intracellular domain. Drk is required for the full activation of transcriptional responses but is dispensable for re-epithelialization. By contrast, Src-family kinases control both the assembly of a contractile actin ring at the wound periphery and Grh-dependent activation of barrier repair genes. Our analysis identifies distinct pathways mediating injury responses and reveals an RTK-dependent activation mode of Src-kinases and their central functions during epidermal wound healing in vivo.