Abstract: Ischemic cardiomyopathy (ICM) remains a major cause of heart failure despite successful epicardial revascularization. Coronary/cardiac microvascular endothelial cells (CMECs) govern tissue-level reperfusion, vasomotor tone, barrier integrity, coagulation and vascular-myocardial communication; their injury therefore links acute microvascular obstruction (MVO)/no-reflow with chronic coronary microvascular dysfunction, capillary rarefaction and adverse remodeling. This review synthesizes evidence linking hypoxia-inducible signaling, endothelial nitric oxide synthase uncoupling, calcium-mitochondrial stress, regulated cell death, endothelial-to-mesenchymal transition-like activation, extracellular-vesicle (EV) communication and thrombo-inflammatory plugging to CMEC dysfunction. Human imaging and pathology are considered alongside endothelial-specific and translational models to distinguish direct microvascular endothelial mechanisms from findings derived from whole-heart or cardiomyocyte systems. Natural products and traditional Chinese medicine-derived interventions are evaluated according to their molecular targets, cellular evidence and effects on microvascular injury. Pyroptosis, ferroptosis and autophagy intersect through mitochondrial reactive oxygen species, iron-dependent lipid peroxidation, inflammasome activation and mitophagy-lysosomal flux, converging on barrier disruption, vasomotor dysfunction and capillary obstruction. EV studies reveal bidirectional signaling among endothelial, myocardial and immune compartments, with context-dependent cargo effects on inflammation, angiogenesis and tissue repair. Invasive physiology and perfusion imaging can identify acute MVO and chronic coronary microvascular dysfunction, whereas molecular RCD and EV signatures remain exploratory. Natural products show multi-target endothelial protection in preclinical models, but direct CMEC evidence and clinical confirmation remain limited.