<p>Valvular heart disease (VHD) and atrial fibrillation (AF) often coexist and lead to a prothrombotic state that necessitates the use of anticoagulants for the prevention of thromboembolic events. Direct oral anticoagulants (DOACs) are a significant advancement in anticoagulation therapy for patients with AF and VHD, leading to comparable efficacy and improved safety outcomes compared to vitamin K antagonists (VKAs). However, their role in patients with severe mitral stenosis, mechanical heart valves, and rheumatic heart disease remains limited due to the lack of robust data from clinical trials. As such warfarin continues to be the anticoagulant of choice for these populations. For patients with bioprosthetic valves or following transcatheter aortic valve implantation (TAVI), DOACs may be a viable alternative, but individualized risk assessment is crucial. The EHRA classification provides a practical framework for the management of patients with AF, but there are still challenges in its clinical application due to mixed valvular pathologies and patient-specific factors. Clinicians must carefully weigh the risk of thromboembolic and bleeding events, consider the patients’ preferences, and advise regular follow-up to optimize the treatment outcomes. Overall, while DOACs offer convenience and similar efficacy and safety compared to VKAs, VKAs remain the anticoagulant of choice for specific subgroups, underscoring the need for personalized approaches regarding anticoagulation therapy.</p>