The expression of caveolin-1 (Cav1) in corneal epithelium is associated with regeneration potency. We used Cav1^-/- mice to study the role of Cav1 in modulating corneal wound healing. Western blot and whole cell patch-clamp were employed to study the effect of Cav1 deletion on Kir4.1 current density in corneas. We found that Ba²⁺-sensitive K⁺ currents in primary cultured murine corneal epithelial cells (pMCE) from Cav1^-/- were dramatically reduced (602pA) in comparison to those from WT (1300pA). As a consequence, membrane potential was elevated in pMCE from Cav1^-/- comparing to that from WT (-43±7.5 vs -58±4.0 mV, respectively). Western blot showed that either inhibition of Cav1 expression or Ba²⁺ incubation stimulated phosphorylation of EGFR. The transwell migration assay showed that Cav1 genetic inactivation accelerated cell migration. The regrowth efficiency of human corneal epithelial cells (HCE) transfected with siRNA-Cav1 or negative control was evaluated by scrape injury assay. With the presence of mitomycin C (10 µg/ml) to avoid the influence of cell proliferation, Cav1 inhibition with siRNA significantly increased migration as compared to control siRNA in HCE. This promoting effect by siRNA-Cav1 could not be further enhanced by cotransfection with siRNA-Kcnj10. By using corneal debridement, we found that wound healing was significantly accelerated in Cav1^-/- compared to WT mice (70±10% vs 36±3%, p<0.01). Our findings imply that the mechanism by which Cav-1 knockout promotes corneal regrowth is, at least partially, due to the inhibition of Kir4.1 which stimulates EGFR signaling.