Elderly individuals and chronic kidney disease (CKD) patients are at a higher risk of acute kidney injury (AKI). The transcription factor MondoA is downregulated in the kidneys of aged or AKI patients; however, its roles in AKI development and the AKI-to-CKD transition remain unknown. We investigated the expression of MondoA in human kidney biopsy samples, ischemia-reperfusion (I/R)-injured mouse kidneys, and cultured proximal tubular epithelial cells under hypoxia/reoxygenation. The role of MondoA during the initial and recovery phases after I/R injury was evaluated using proximal tubule-specific MondoA knockout mice and MondoA-deficient proximal tubular epithelial cells. Furthermore, we explored the involvement of Rubicon and transcription factor EB (TFEB), both of which are downstream factors of MondoA. MONDOA expression was decreased in the renal tubules of CKD patients. In mouse kidneys, MondoA expression was decreased under ischemia, while its expression was increased during reperfusion. Genetic ablation of MondoA in proximal tubular epithelial cells inhibited autophagy and increased vulnerability to AKI through increased expression of Rubicon. Ablation of Rubicon in MondoA-deficient I/R-injured kidneys activated autophagy and protected mitochondrial function. MondoA ablation during the recovery phase after I/R aggravated kidney injury through downregulation of the TFEB-PGC1α axis. Pharmacological upregulation of TFEB contributed to maintaining mitochondrial biogenesis and increased PGC1α transcription. Our findings demonstrate that MondoA protected against vulnerability to AKI by maintaining autophagy and subsequently supporting mitochondrial function to prevent progression to CKD.