In patients with atrial fibrillation (AF) who undergo an acute coronary syndrome (ACS), with or without percutaneous coronary intervention and coronary stent implantation, the association of dual antiplatelet therapy with an oral anticoagulant (also known as triple antithrombotic therapy, TAT) increases the risk for major and fatal bleeding. Recently, several trials have evaluated alternative therapeutic regimens to TAT, such as dual antithrombotic therapy (DAT) comprising a direct oral anticoagulant and a platelet P2Y12 receptor inhibitor. In the context of patients treated with percutaneous coronary intervention, these regimens have generally been associated with a reduction in bleeding that was not accompanied by a substantial increase in ischemic events. However, the net benefit of DAT is more controversial in the case of patients at higher thrombotic risk, such as patients with ACS. This review, based on the available literature, describes the best peri-procedural and post-procedural antithrombotic strategies for patients with AF and ACS.