The gastrointestinal tract (GI) has a unique oxygenation profile. It should be noted that the state of hypoxia can be characteristic of both normal and pathological conditions. Hypoxia-inducible factors (HIF) play a key role in mediating the response to hypoxia, and they are tightly regulated by a group of enzymes called HIF prolyl hydroxylases (PHD). In this review, we discuss the involvement of inflammation hypoxia and signaling pathways in the pathogenesis of inflammatory bowel disease (IBD) and elaborate in detail on the role of HIF in multiple immune reactions during intestinal inflammation. We emphasize the critical influence of tissue microenvironment and highlight the existence of overlapping functions and immune responses mediated by the same molecular mechanisms. Finally, we also provide an update on the development of corresponding therapeutic approaches that would be useful for treatment or prophylaxis of inflammatory bowel disease.