Peripheral artery disease (PAD) is a prevalent manifestation of atherosclerosis, characterized by stenosis or occlusion of peripheral arteries, predominantly affecting the lower extremities. It is associated with systemic atherosclerosis, often coexisting with coronary artery disease (CAD). The pathophysiology of PAD involves endothelial dysfunction, lipid accumulation, and chronic inflammation, which contribute to arterial narrowing, ischemia, and an increased risk of cardiovascular events such as myocardial infarction and stroke. Atherosclerosis, the underlying pathology of PAD, is a progressive inflammatory disease driven by endothelial dysfunction and immune cell infiltration. Plaque development involves lipid deposition, smooth muscle cell proliferation, and extracellular matrix remodeling. Platelets play a crucial role in the development and progression of atherosclerosis by interacting with endothelial cells, leukocytes, and extracellular matrix components. Through glycoprotein receptors and adhesion molecules, platelets promote leukocyte recruitment, enhance inflammation, and contribute to plaque progression. Their release of pro-inflammatory cytokines and growth factors accelerates vascular remodeling, while platelet-derived microparticles and extracellular vesicles further propagate inflammatory signaling within the plaque microenvironment. In PAD, platelet hyperreactivity exacerbates thrombotic risk, particularly in high-risk individuals or those undergoing revascularization procedures. Emerging evidence highlights the differential involvement of platelets in distinct vascular beds, with variations in plaque composition and stability influencing thrombotic outcomes. Understanding the mechanisms governing platelet activation in PAD is essential for optimizing therapeutic strategies. Antiplatelet therapy, including aspirin and P2Y12 inhibitors, remains the cornerstone of PAD management. However, high-on-treatment platelet reactivity (HTPR) poses a challenge, contributing to thrombotic events despite pharmacologic intervention. The identification of novel platelet biomarkers offers promising avenues for personalized antiplatelet therapy in PAD.