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Omentin-1 is an adipokine predominantly secreted by visceral adipose tissue (VAT) and is abundant in human plasma. Circulating omentin-1 levels are significantly reduced in patients with obesity, type 2 diabetes mellitus (T2DM), hypertension, and coronary artery disease (CAD). However, the associations between circulating omentin-1 levels and cardiovascular risk and prognosis appear heterogeneous across populations and disease stages. Accumulating evidence indicates that omentin-1 exerts multiple cardioprotective effects. These effects include anti-atherosclerotic activity, improved insulin sensitivity, anti-inflammatory and antioxidant effects, enhanced endothelial function, and myocardial protection. Through these mechanisms, omentin-1 contributes to vascular and cardiometabolic homeostasis. This review summarizes the biological characteristics of omentin-1 and its protective roles and molecular mechanisms in CVD. It also highlights recent advances in clinical research. We further highlight emerging evidence that commonly used cardiometabolic drugs can modulate omentin-1 levels, supporting its potential as both a biomarker and a therapeutic target. A clearer understanding of its pleiotropic actions may facilitate the development of translational strategies for CVD prevention and treatment.