Despite accumulating evidence revealing susceptibility genes for age-related cataract, its pathophysiology leading to visual impairment at the cellular and molecular level remains poorly understood. Recent bioinformatic studies uncovered the association of two single nucleotide polymorphisms in human EPHA2, rs2291806 and rs1058371, with age-related cataract. Here we investigated the role of EPHA2 in counteracting oxidative stress-induced apoptosis of lens epithelial cells. The cataract-associated missense mutations resulted in the destabilization of EPHA2 receptor without altering the mRNA transcription. The cytoprotective and antiapoptotic function of EPHA2 in lens epithelial cells was abolished by the functional polymorphisms. Furthermore, our results suggest that the downstream signaling of activated EPHA2 promotes the antioxidative capacity of lens epithelial cells to eradicate the overproduction of reactive oxygen species. In contrast, the overexpression of EPHA2 with nonsynonymous mutations in the lens epithelial cells offered limited antioxidative protection against oxidative stress. Thus, our study not only sheds the light on the potential cytoprotective function of EPHA2 signaling in lens but also provides the cellular mechanisms underlying the pathogenesis of age-related cataract.