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The primary etiology of chronic kidney disease is a direct consequence of initial glomerular dysfunction. Podocytes (visceral glomerular epithelial cells) in normal mature kidneys are regarded as highly differentiated and quiescent cells. Krüppel‐like factors (KLFs), zinc‐finger DNA‐binding transcription factors, play a critical role in podocyte biology. Specifically, KLF6 expression was reduced in models of podocyte injury. Podocyte‐specific loss of Klf6 ( Cre + podocin Klf6 flox/flox ) in mice resulted in significant albuminuria and podocyte injury with adriamycin (ADR) treatment (a model of podocyte injury). ADR‐treated Cre + podocin Klf6 flox/flox mice also exhibited dysmorphic mitochondria in the podocytes and promoter analysis revealed putative binding sites for KLF6 on cytochrome c oxidase assembly gene ( SCO2 ). KLF6 expression increased within 6 hours of ADR (0.4μg/μl) treatment in human podocytes (HP). Knockdown of KLF6 (shRNA‐ KLF6 ) in HP reduced the mitochondrial membrane potential as compared to shRNA‐EV HP (control). ADR‐treated shRNA‐ KLF6 HP increased mitochondrial fragmentation with reduced SCO2 expression and ATP levels. Also, ADR‐treated shRNA‐ KLF6 increased cleaved‐caspase 3, 9, and cytosolic cytochrome c expression and decreased pro‐caspase 3 expression. These changes were restored after reintroduction of KLF 6 in HP. Also, knockdown of SCO2 (shRNA‐ SCO2 ) increased cytosolic cytochrome c and cleaved‐caspase 9 levels. Finally, immunostaining revealed a reduction in podocyte‐specific KLF6 expression in biopsies from patients with glomerular disease. These findings suggest that KLF6 is an early inducible injury response gene, critical to the maintenance of mitochondrial function and preventing the activation of the intrinsic apoptotic pathway upon cell stress.