Hypoxia-inducible factors (HIFs) are master regulators of cellular adaptation to hypoxia in both disease and normal physiological conditions. HIFs consist of two subunits: the oxygen-sensitive alpha (α) and the constitutively expressed beta (β). The three oxygen-dependent alpha subunits-HIF-1α, HIF-2α, and HIF-3α-encoded by distinct genes are crucial for regulating cellular responses to hypoxia in various vertebrates, including humans. Much of our understanding of HIFs is based on studies on HIF-1α and HIF-2α subunits. Recent studies have shown that, although HIF-3α is the least studied member, it may also play essential roles in the development of human diseases, including cancer, cardiovascular and respiratory diseases, metabolic disorders, and other pathological processes. In this review, we focus on how HIF-3α overexpression is associated with various human diseases, aiming to better understand its role in human pathophysiology and its potential use as a therapeutic target.