Protease activated receptor 4 (PAR4) is a key target in antiplatelet medication to reduce the risk of heart attack and thrombotic complications in stroke. PAR4 antagonists can prevent harmful and stable thrombus growth while retaining initial thrombus formation by acting on the late diffusion stage of platelet activation, which may provide a safer alternative than other antiplatelet agents. Currently, research on PAR4 antagonists is of increasing interest in the field of antiplatelet agents. This article provides an overview of the discovery and development of small-molecule antagonists of PAR4 as novel antiplatelet agents, including structure-activity relationship (SAR) analysis, progress of structure and bioassay optimization, and the latest structural and/or clinical information of representative small-molecule antagonists of PAR4.