Cardiorenal syndrome (CRS) represents a heterogeneous clinical entity characterized by complex, bidirectional interactions between the cardiovascular system and the kidneys, in which acute or chronic dysfunction of one organ precipitates or aggravates injury to the other. Recently, the concept has been broadened to the cardiovascular–kidney–metabolic (CKM) syndrome, emphasizing the central role of metabolic risk factors, chronic inflammation, and systemic dysregulation in disease initiation and progression. The pathophysiology of CRS extends beyond simple hemodynamic compromise and involves a multifaceted interplay of venous congestion, impaired cardiac output, neurohormonal activation, inflammatory and oxidative pathways, mitochondrial dysfunction, and maladaptive cellular signaling. Elevated central venous and intra-abdominal pressures have emerged as key determinants of renal injury, while pro-inflammatory cytokines, oxidative stress, and fibrosis drive parallel damage in both organs. Advances in molecular biology and multi-omics approaches have further revealed shared transcriptional, proteomic, and metabolic alterations across CRS subtypes, highlighting common mechanistic pathways irrespective of the direction of organ injury. In parallel, novel therapeutic strategies—including sodium–glucose cotransporter-2 inhibitors, vasopressin antagonists, anti-inflammatory agents, and mitochondria-targeted therapies—have demonstrated promising cardiorenal protective effects, although disease-specific trials remain limited. A comprehensive understanding of the underlying pathophysiological mechanisms is essential to enable earlier diagnosis, refine risk stratification, and develop targeted therapies aimed at improving outcomes in patients with combined cardiac and renal dysfunction.