<p>Diabetic kidney disease (DKD) is one of the common and devastating chronic complications of diabetes, its pathogenesis remains incompletely understood. Emerging evidence suggests that mitochondrial dysfunction plays a crucial role in the onset and progression of DKD. Mitochondrial transcription factor A (TFAM), a key regulator of mitochondrial DNA (mtDNA) expression, is essential for maintaining mitochondrial integrity and function, and is increasingly recognized for its role in modulating inflammatory signaling. This review focuses on the regulatory mechanisms by which TFAM stabilizes mitochondrial function and prevents mtDNA leakage, thereby inhibiting activation of the cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway. Suppression of this pathway has been shown to alleviate renal inflammation and fibrosis. Given the current lack of curative therapies for DKD, targeting the TFAM–cGAS–STING signaling axis represents a promising novel strategy for both therapeutic intervention and mechanistic research in DKD.</p>