Recent clinical and animal studies have shown that acute kidney injury (AKI), even if followed by complete recovery of renal function, can eventually result in chronic kidney disease (CKD). Renal hypoxia is emerging as a key player in the pathophysiology of the AKI-to-CKD transition. Capillary rarefaction after AKI episodes induces renal hypoxia, which can in turn profoundly affect tubular epithelial cells, (myo)fibroblasts, and inflammatory cells, culminating in tubulointerstitial fibrosis, i.e., progression to CKD. Damaged tubular epithelial cells that fail to redifferentiate might supply a decreased amount of vascular endothelial growth factor and contribute to capillary rarefaction, thus aggravating hypoxia and forming a vicious cycle. Mounting evidence also shows that epigenetic changes are closely related to renal hypoxia in the pathophysiology of CKD progression. Animal experiments suggest that targeting hypoxia is a promising strategy to block the transition from AKI to CKD. However, the precise mechanisms by which hypoxia induces the AKI-to-CKD transition and by which hypoxia-inducible factor activation can exert a protective effect in this context should be clarified in further studies.