Heparin is among the most widely used anticoagulants worldwide, with an annual market of ∼$4 billion. It also poses potential bleeding risks (0.5–5%), occasionally life-threatening, necessitating heparin reversal agents. Protamine sulfate is the only approved agent to reverse heparin for overdose, bleeding, cardiopulmonary bypass, or urgent surgical intervention. However, its efficacy is limited against low-molecular-weight heparin (LMWH) and negligible against ultralow-molecular-weight heparin (ULMWH). Additional concerns include allergic reactions, hypotension, and sourcing constraints, underscoring the need for safe and effective alternatives. In recent years, diverse novel heparin reversal agents have emerged, spanning proteins/peptides, cationic macromolecules, nanoparticles, gels, and small molecules, yet a medicinal-chemistry-oriented analysis of these agents remains lacking. In this perspective, we critically summarize design strategies, structural features, and biological activities of reported heparin reversal agents, and discuss key challenges and future directions to inform the development of novel antidotes.