<p>Regular physical exercise can induce a multifaceted cardioprotective phenotype characterized by improved Ca²⁺ handling, mitochondrial resilience, redox buffering, autonomic regulation, and resistance to ischemia–reperfusion injury. Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), particularly cardiac CaMKIIδ, is positioned at the intersection of these adaptive and maladaptive responses because it couples repetitive Ca²⁺ oscillations to excitation–contraction coupling, ion-channel regulation, transcriptional remodeling, mitochondrial stress signaling, and cell-death pathways. Current evidence indicates that CaMKII is not intrinsically protective or harmful; rather, its biological output depends on activation magnitude, duration, post-translational modification, isoform or splice-variant composition, and subcellular localization. Within physiological exercise contexts, transient and compartmentalized CaMKII signaling may support rate adaptation, phospholamban phosphorylation, sarcoplasmic reticulum Ca²⁺ reuptake, and contractile reserve. In contrast, chronic oxidative, inflammatory, catecholaminergic, or metabolic stress promotes autonomous CaMKII activation, RyR2-mediated Ca²⁺ leak, late Na⁺ current, mitochondrial dysfunction, arrhythmogenesis, and adverse remodeling. Exercise training appears to normalize this pathological signaling environment by improving redox and metabolic homeostasis, mitochondrial quality control, nitric oxide bioavailability, and autonomic balance, while preserving physiological CaMKII-dependent cardiac reserve. In this review, we synthesize current evidence on CaMKII as a context-dependent mediator of exercise-induced cardioprotection and discuss its implications for cardiovascular disease mechanisms, biomarker development, exercise prescription, and selective CaMKII-targeted therapy.</p> Graphical Abstract <p></p>