Platelet–endothelial interactions are fundamental to vascular health, spanning hemostasis, immunity, and tissue repair. Platelets, as first responders, orchestrate the transition from vascular injury to recovery by adhering to exposed subendothelial components and releasing bioactive factors. This dynamic interplay involves von Willebrand factor (VWF), thrombin generation, and integrin-mediated adhesion, which stabilize the platelet plug and promote coagulation. Beyond clot formation, platelets play key roles in immune cell recruitment, angiogenesis, and maintain endothelial integrity. However, dysregulated platelet activation contributes to vascular pathologies such as atherosclerosis and chronic inflammation. Organ-specific endothelial traits, such as varied VWF expression, further shape these interactions, influencing susceptibility to thrombotic complications. Advances in engineered vascular systems have provided insights into platelet–endothelium interactions under physiological flow, revealing the complexity of site-specific thrombosis and endothelial heterogeneity. This review explores the multifaceted roles of platelets in vascular safeguarding, highlighting their contributions to homeostasis and their dual potential to drive repair or disease in the vascular system.