The anticoagulant proteins antithrombin, protein C, protein S, and tissue factor pathway inhibitor are physiological regulators of the blood coagulation pathway and have complex roles in causing or modifying the severity of bleeding and clotting disorders. The anticoagulant activity, as well as alternative physiological functions, of these proteins also impact many other diseases beyond bleeding and clotting disorders. We searched PubMed for articles published between 2018 and early 2025 that pertained to alternative functions of these physiological anticoagulants in clinical disease and selected therapeutic applications in the following categories: cancer, cardiovascular disease, novel therapeutics, pregnancy health, inflammation and infection, blood-brain barrier protection, stroke, novel developments in thrombosis, and endothelial and platelet interactions. This review highlights recently identified physiological implications of antithrombin, protein C, protein S, and tissue factor pathway inhibitor functions that present an exciting therapeutic avenue for a diverse array of human diseases.