The mechanisms involved in the cardiovascular–renal–metabolic (CKM) syndrome include the accumulation of visceral and ectopic fat in organs such as skeletal muscle, which promotes insulin resistance, systemic inflammation, and oxidative stress; these factors contribute to muscle protein degradation and muscle mass loss. Additionally, skeletal muscle, being the primary consumer of glucose and a major protein reservoir, plays a crucial role in maintaining energy and metabolic homeostasis. Functional deficiencies in skeletal muscle can disrupt systemic metabolic balance, thereby increasing the risk of chronic diseases. Sarcopenia has been recognized as a central component of CKM syndrome. Muscle mass loss leads to a reduction in insulin sensitivity, exacerbating metabolic dysfunction and worsening diabetes. On the other hand, renal dysfunction results in the accumulation of uremic toxins, which accelerate muscle degradation, thereby perpetuating the vicious cycle. Also, sarcopenia is associated with reduced functional capacity and an increased risk of heart failure and mortality. In CKM syndrome, sarcopenia results from a complex interaction between oxidative stress, low-grade chronic inflammation, hormonal dysfunction, and alterations in insulin signaling pathways, all of which affect the balance between muscle protein synthesis and degradation. Dysregulation of autophagy, along with insulin resistance, lipotoxicity, and mitochondrial dysfunction, contributes to progressive muscle degradation and the loss of muscle mass and function. Sarcopenia is a major risk factor for heart failure, arrhythmias, and sudden cardiac death (SCD), and when it coexists with cardiac dysfunction, it significantly increases the risk of mortality and hospitalizations. Furthermore, sarcopenia and sarcopenic obesity (SO) are associated with metabolic disorders and insulin resistance, contributing to the development of type 2 diabetes (T2D). In chronic kidney disease (CKD), the accumulation of uremic toxins promotes insulin resistance and muscle atrophy, worsening metabolic and cardiovascular deterioration. Therapeutic interventions, including personalized physical exercise, adequate nutrition, combined treatment with innovative medications such as SGLT2 inhibitors and GLP-1 receptor agonists, amino acid supplements, and emerging interventions (genetic and stem cell therapies), offer new perspectives for managing sarcopenia and its associated conditions.