The development of new antiplatelet drugs is critical for improving the management of cardiovascular diseases, where platelet aggregation plays a pivotal role in thrombus formation and vascular occlusion. G-protein–coupled receptors (GPCRs) are key regulators of platelet function and are involved in various signaling pathways that influence platelet activation, aggregation, and thrombus formation. This review explores the role of GPCR signaling in platelets and its implications for the development of novel antiplatelet therapies. We highlight the mechanisms by which GPCRs, such as P2Y receptors and thrombin receptors, modulate platelet activity and contribute to the pathogenesis of thrombotic events. The review also examines recent advancements in the design of GPCR-targeted therapies, including small molecules, monoclonal antibodies, and receptor antagonists, aimed at enhancing platelet inhibition while minimizing bleeding risks. Additionally, we discuss the challenges and future directions for integrating GPCR-targeted strategies into clinical practice for more effective prevention and treatment of thromboembolic disorders.