The process of wound healing must be tightly regulated to achieve successful restoration of injured tissue. Previously, we demonstrated that when injury to corneal epithelium occurs, nucleotides and neuronal factors are released to the extracellular milieu, generating a Ca²⁺ wave from the origin of the wound to neighboring cells. In the present study we sought to determine how the communication between epithelial cells in the presence or absence of neuronal wound media is affected by hypoxia. A signal-sorting algorithm was developed to determine dynamics of Ca²⁺ signaling between neuronal and epithelial cells. The crosstalk between activated corneal epithelial cells in response to neuronal wound media demonstrated that injury-induced Ca²⁺ dynamic patterns were altered in response to decreased oxygen levels. These alterations were associated with an overall decrease in ATP, and changes in purinergic receptors-mediated Ca²⁺ mobilization and localization of N-methyl-D-aspartate (NMDA) receptors. In addition we used the cornea in an organ culture wound model to examine how hypoxia impedes re-epithelialization after injury. There was a change in the recruitment of paxillin to the cell membrane and deposition of fibronectin along the basal lamina, both factors in cell migration. Our results provide evidence that complex Ca²⁺-mediated signaling occurs between sensory neurons and epithelial cells after injury and is critical to wound healing. Information revealed by these studies will contribute to an enhanced understanding of wound repair under compromised conditions and provide insight into ways to effectively stimulate proper epithelial repair.