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Thrombospondin-2 (TSP-2) is an extracellular matrix glycoprotein involved in angiogenesis, vascular remodeling, cell adhesion, and tissue repair. Its expression is induced by pathological stimuli, including mechanotransduction, hypoxia, and TGF-β signaling, and has been associated with several cardiovascular diseases (CVDs), such as heart failure, coronary artery disease, abdominal aortic aneurysm, and hypertension. Elevated circulating TSP-2 levels, particularly in combination with NT-proBNP, as well as alterations in THBS2 and its regulatory non-coding RNAs, have been linked to disease severity and adverse cardiovascular outcomes. This review summarizes current evidence on the role of TSP-2 in cardiovascular pathophysiology and its involvement in cardiovascular homeostasis. Although accumulating data suggest that TSP-2 may have diagnostic, prognostic, and therapeutic relevance, its clinical utility as a biomarker or therapeutic target has not yet been established. Further large-scale studies and standardized assessment methods are required to validate its potential and support future clinical translation.