Percutaneous left atrial appendage closure (LAAC) has been established in clinical practice as an attractive alternative to oral anticoagulation for preventing stroke in patients with atrial fibrillation and high bleeding risk. The devices approved in Europe and United States (US) for percutaneous LAAC contain metal and antithrombotic therapy is strongly recommended after their implantation to prevent apposition of thrombus on the atrial surface of the device during endothelialization. However, there is still uncertainty regarding the optimal antithrombotic drug regimen following device implantation in view of the incomplete understanding of the LAAC device healing process, the lack of randomized clinical trials comparing different antithrombotic agents after LAAC and the heterogeneous bleeding risk of patients undergoing LAAC. Thus, this review aims to evaluate the available evidence and the remaining challenges related to the post-LAAC antithrombotic regimens. Furthermore, common clinical scenarios associated with challenging management of antithrombotic therapy after LAAC and potential future directions, will be discussed.