Porcine epidemic diarrhea (PED), caused by porcine epidemic diarrhea virus (PEDV), is an acute and contagious enteric disease with high mortality in sucking piglets, causing huge economic losses to swine industry. In this study, we used tandem mass tag (TMT) quantitative protein analysis to investigate the proteomic changes of PK15 cells after PEDV infection, and the differential protein expression profiles were obtained at 0 h, 24 h, and 48 h after PEDV infection