Apolipoprotein E (apoE = protein; APOE = encoding gene) is a key player in cholesterol metabolism with systemic immunomodulatory effects. APOE4, which encodes the apoE4 isoform, is associated with hypercholesterolemia and a marked increase in the risk of acquiring late-onset Alzheimer’s disease and developing atherosclerosis. Although more research has been devoted to better understanding the effect of apoE in the nervous and cardiovascular systems, few studies have addressed the role of apoE in the intestinal barrier function, especially regarding the intestinal lining epithelium. The intestinal epithelium permeability is increased in various gut inflammatory conditions, often associated with intestinal microbiota dysbiosis, which leads to bacterial translocation and systemic inflammation, a common cause of chronic debilitating diseases. In this chapter, we summarize the apoE effects on the intestinal epithelium in vitro and in vivo studies following intestinal injury and the crosstalk with the intestinal microbiota. We also reviewed the importance of APOE polymorphisms in children afflicted with heavy burdens of diarrhea and malnutrition early in life. Finally, we discuss the role of APOE4 in environmental enteropathy under adverse environments and call attention to the importance of apoE research to improve intestinal epithelial recovery in various intestinal inflammatory conditions.