Heart failure (HF) represents a heterogeneous condition characterized by vulnerabilities in the blood, vasculature, and impaired flow dynamics that predispose to both arterial and venous thrombosis. Despite evidence-based advances in the medical and device management of chronic HF, it remains a leading cause of morbidity and mortality in the USA due to repeat hospitalizations and comorbid conditions such as atrial fibrillation (AF) and stroke. The presence of platelet activation and hypercoagulability in HF has been well documented. Anticoagulation is effective in HF when comorbidities such as AF and prior venous thromboembolism exist. However, data is less clear for HF in sinus rhythm. Moreover, there is a paucity of data regarding antiplatelet therapy in HF. No consensus guidelines exist regarding the precise role of antiplatelet or antithrombotic therapy in HF. This review addresses the pathophysiology of coagulation abnormalities in HF, examines the available evidence regarding the use of anticoagulants and antiplatelet agents in HF, and discusses its therapeutic implications.