Porcine epidemic diarrhea virus (PEDV) causes acute and devastating intestinal disease in suckling piglets, resulting in a huge loss in the worldwide swine industry. Although several researches have reported that PEDV could cause viremia, the mechanism of how PEDV spread in the blood has been still unclear. Here, we showed PEDV could cause typical diarrhea in newborn piglets through hijacking red blood cells (RBCs). Firstly, PEDV could bind and internalize into neonatal RBCs through CD71 and clathrin-mediated endocytosis, and maintain its viability for 12 h. Subsequently, PEDV-loaded RBCs could transfer the virus to CD3+ T cells by formatting conjugation structure. PEDV could continue to hitchhike CD3+ T cells to reach intestine mucosa and cause infection. Moreover, after autotransfusion with PEDV-loaded RBCs, PEDV could infect and colonize intestinal epithelial cells, causing typical diarrhea symptoms in newborn piglets. Unintentionally, PEDV-loaded RBCs were found in nasal capillary after intranasal spraying with PEDV. Since oxygen partial pressure (pO2) and temperature of nasal cavity are different from other tissues, we further determined the higher pO2 was a promoting factor for PEDV binding RBCs. Therefore, the nasal capillary was speculated to be the entry for PEDV binding RBCs. Collectively, our studies illustrated the mechanism that PEDV could cause intestine infection through hijacking RBCs, further providing a novel insight into the role of RBCs in coronavirus pathogenesis as potential cells for viral transmission.