Oxygen supply is crucial to the health of avascular human cornea where low-oxygen-transmissible soft contact lenses often cause keratitis upon excessive wear time. Caffeic acid phenethyl ester, an active component of propolis, has anti-oxidative and anti-inflammatory properties. This study investigated the in vitro effects of caffeic acid phenethyl ester on corneal inflammation and its underlying action. We measured NF-κB activity and Dichloro-dihydro-fluorescein diacetate staining to demonstrate that caffeic acid phenethyl ester ameliorates hypoxia-induced inflammation of corneal endothelial cells and reactive oxygen species formation. The results may provide a new strategy to mitigate keratitis by caffeic acid phenethyl ester treatment.