Venous thromboembolism (VTE) is a common and preventable cause of morbidity and mortality in hospitalized patients. Low-molecular-weight heparin, low-dose unfractionated heparin, fondaparinux, and warfarin have been the mainstay options for the prevention and treatment of VTE before the emergence of nonvitamin K antagonist oral anticoagulants (NOACs) such as dabigatran, rivaroxaban, apixaban, and edoxaban. Despite the advantages of NOACs in improving patient adherence, none of them are approved for the prevention of VTE in acutely ill medical patients at high risk of thromboembolism. Betrixaban is a new NOAC and a factor Xa inhibitor that was approved for extended-duration thromboprophylaxis in these high-risk patients. The approval was based on the results of the APEX (Acute Medically Ill VTE Prevention with Extended Duration Betrixaban) study. In this Phase III randomized controlled trial, once-daily oral betrixaban (35 to 42 days extended duration) was associated with a reduction of composite VTE with no difference in major bleeding when compared to once-daily subcutaneous enoxaparin (6 to 14 days standard duration). Betrixaban differs from other NOACs by having a longer half-life, minimal CYP450 interactions, and minimal renal clearance. This article provides an overview of betrixaban’s pharmacological profile, clinical trial results, and potential roles in therapy.