Interferon regulatory factor 8 () is a key regulator of innate immune receptor signaling that resists pathogen invasion by regulating cell growth and differentiation. Porcine epidemic diarrhea virus (PEDV) targets the intestine and damages the mucosal barrier. However, whether regulates PEDV replication remains unclear. We revealed that PEDV infection activated expression. Moreover, deletion drastically promoted PEDV replication and invasion, increasing the virus copies and titers. Hypomethylation enrichment of activating protein (AP)-2α was significantly negatively correlated with high expression, and AP-2α directly targeted the promoter to regulate PEDV replication. Furthermore, overexpression decreased the cellular reactive oxygen species levels and mitochondrial membrane potential and increased the antioxidant enzyme activities to alleviate PEDV-induced oxidative damage. overexpression suppressed apoptotic gene expression, thereby inhibiting apoptosis in response to PEDV stimulation. Taken together, this study demonstrates that AP-2α is involved in PEDV-induced epigenetic modification of to reduce cell apoptosis and oxidative stress and facilitate host resistance to PEDV in the intestinal epithelium.