Optic neuropathy is associated with retinal ganglion cell (RGC) loss leading to optic nerve damage and visual impairment. Recent research has shown that transient block of connexin43 (Cx43) hemichannels by a Cx43 mimetic peptide (MP), Peptide5, delivered systemically or by intravitreal injection after retinal ischemia inhibits uncontrolled hemichannel opening to provide significantly reduced vessel leak and inflammation as well as significantly enhanced RGC survival. We have previously shown, in vitro, that a chemically modified C12-C12-Cx43 MP has a twofold greater half-life in bovine vitreous (ex vivo) than the native peptide. The present study investigated the ability of intravitreally injected, chemically modified C12-C12-Cx43 MP to further enhance RGC survival in a rat retinal ischemia-reperfusion model. Intravitreally injected native Cx43 MP or C12-C12-Cx43 MP both minimized vessel leak, reduced inflammation, and protected RGC after ischemic injury. However, the modified C12-C12-Cx43 MP, with its prolonged vitreous stability, showed significantly lower levels of Cx43 expression post-injury, with a trend towards a greater reduction in vessel leak and further RGC protection, suggesting that these molecules may be a clinically relevant neuroprotective tool in the treatment of optic neuropathy.