The American Heart Association (AHA) recently formalized cardiovascular-kidney-metabolic (CKM) syndrome to characterize the systemic interplay among cardiovascular failure, chronic kidney disease (CKD), and metabolic disturbances. Despite evolving clinical management, identifying a unifying cellular driver of this multi-organ deterioration remains a critical priority. This review explores the hypothesis that mitochondrial dysfunction serves as the fundamental pathological nexus of CKM syndrome, driving the progression from early-stage metabolic risk to end-stage organ failure. We synthesize evidence demonstrating how nutrient overload and lipotoxicity precipitate a vicious cycle of bioenergetic failure. In the cardiovascular system, ATP deficiency and impaired mitophagy lead to the structural remodeling observed in both heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). In the kidney, the high mitochondrial density of proximal tubules renders them uniquely susceptible to oxidative stress and mitochondrial DNA (mtDNA) leakage, which subsequently triggers systemic inflammation. Furthermore, we analyze how established therapies-including sodium-glucose co-transporter 2 (SGLT2) inhibitors, Glucagon-like peptide-1 (GLP-1) receptor agonists, and non-steroidal mineralocorticoid receptor antagonists (MRAs)-exert organ-protective effects via mitochondrial mechanisms, promoting metabolic efficiency, reducing reactive oxygen species generation, stabilizing mitochondrial integrity, and promoting mitochondrial quality control processes. Finally, we review emerging mitochondrial-targeted strategies, such as mitoquinol, elamipretide and NAD+ boosters, which aim to restore the SIRT1-PGC-1 α signaling axis. Mitochondria function as the central engines of the CKM axis. A shift toward a mitocentric clinical model may enable earlier intervention and more precise targeting of the mechanisms driving organ crosstalk. Future success depends on multidisciplinary collaboration and the validation of mitochondrial biomarkers to advance precision medicine in CKM syndrome.