Protamine is a routinely used safe antidote for heparin reversal in cardiovascular surgery. Protamine was first utilized to extend the shelf life of insulin formulations. Only a little amount of protamine is used to neutralize heparin in plasma because it interacts with platelets and fibrinogen while still serving as an anticoagulant. Major Adverse Drug Reactions (ADRs) have been related to protamine; however they are uncommon, especially in patients with a history of protamine hypersensitivity. Protamine-induced pulmonary arterial hypertension and peripheral vascular collapse struck a 60-year-old diabetic male patient who had had on-pump coronary artery bypass grafting at a tertiary care center. This was a definite, non-preventable, severe ADR, according to the causality, preventability, and severity assessment scale.