Over the past decade, non-vitamin K antagonist oral anticoagulants have revolutionized anticoagulation therapy, offering substantial benefits over traditional vitamin K antagonists. Non-vitamin K antagonist oral anticoagulants offer reduced bleeding risks, fixed dosing without frequent monitoring, and fewer drug and dietary interactions. Their effectiveness has been demonstrated in preventing stroke in atrial fibrillation, managing venous thromboembolism, and offering new options for patients with coronary artery disease and cancer-associated thrombosis. However, challenges remain, including bleeding risks, high costs, and limited efficacy in certain patient populations. Current research is focused on addressing these limitations, with Factor XI inhibitors emerging as a promising advancement for safer anticoagulation. This review provides an overview of the clinical highlights, challenges, and future directions of anticoagulation therapy.