The present study provides the first systematic analysis of the global protein profiles of PDCoV-infected IPEC-J2 cells using a quantitative proteomics approach in which iTRAQ was coupled to LC-MS/MS. A total of 78 DEPs, including 23 upregulated proteins and 55 downregulated proteins, were identified in PDCoV-infected IPEC-J2 cells at 24 hpi. Bioinformatics analyses further revealed that a majority of the DEPs were involved in various crucial biological processes and signaling pathways, such as digestive system, immune system, signal transduction, and RIG-I-like receptor, mTOR, PI3K-AKT, autophagy, and cell cycle signaling pathways. Although further investigations are required to elucidate the functions of the DEPs of interest, our current data provide valuable clues for the in-depth investigation of pathogenic mechanisms of PDCoV and defense mechanisms of host cells.