The screening and identification of porcine epidemic diarrhea virus (PEDV) host restriction factors are of great significance for the prevention, control and treatment of porcine epidemic diarrhea (PED), but due to the lack of a suitable research platform, this field has been progressing slowly. In this study, label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to quantitatively identify the differentially expressed proteins (DEPs) between porcine kidney cell lines LLC-PK1 and PK15, whose susceptibility to PEDV was distinct. We identified 118 and 69 specific expressed proteins (fold changes >20 and with p < 0.05) in LLC-PK1 and PK15 cells, respectively. In addition, another 1138 DEPs, including 652 upregulated and 486 downregulated proteins, were identified in LLC-PK1 cells. Alterations in the expression of selected proteins were verified by western blot. Bioinformatics analyses, including GO, KEGG, and STRING, further demonstrated that the DEPs are involved in numerous crucial biological processes and signaling pathways, such as organelle organization, nucleotide binding, phagosome, lysosome, focal adhesion pathways and metabolic pathways. Altogether, this is the first proteomic study of porcine cell lines with high homology but different infectivity to PEDV, which shall provide valuable clues for further investigation of PEDV pathogenesis.