If atrial fibrillation (AF) and acute coronary syndrome (ACS) coexist, they should be treated with combined antithrombotic therapy. To reduce the risk of bleeding while maintaining the desired antithrombotic effect, choices should be made for each patient according to the balance between the bleeding and the thrombotic risk. There are many ways to select the type and dose of the oral anticoagulant (OAC) and P2Y12 inhibitors. As a rule of thumb, aspirin and P2Y12 inhibitors should be recommended to all patients. The duration of this combination therapy is a matter of debate; available data promote an initial period of one to four weeks of triple antithrombotic association with aspirin and P2Y12 inhibitors (clopidogrel in the absence of high ischaemic risk) and preferable direct oral anticoagulants (DOACs). On discontinuing aspirin, double therapy with P2Y12 inhibitors and a DOAC provides similar efficacy and superior safety for many patients on ACS medical or interventional treatment, especially if the risk of bleeding is high and that of thrombosis is low. Further studies are needed to clarify the concerns for a slight augmentation in the number of ischaemic cases (myocardial infarction and stent thrombosis) with double antithrombotic regimen in patients at high ischaemic risk.