The prescription appropriateness of direct oral anticoagulants (DOACs [dabigatran, rivaroxaban, apixaban, and edoxaban]) is carefully regulated, taking into account the criteria established in phase III trials and listed in the summary of the product characteristics of the four DOACs. In clinical practice, prescriptions are not always in compliance with established indications. In particular, the use of doses lower than those recommended in drug data sheets is relatively frequent. Literature data show that the inappropriate prescription of DOAC doses causes drug underexposure and an up to three-fold increase in the risk of stroke/transient ischemic attack, systemic thromboembolism, and hospitalizations. Possible causes of the deviation between the dose that should be prescribed and that actually employed may include erroneous prescriptions, an overstated bleeding risk perception, and the presence of frail patients, who were not included in pivotal trials. For these reasons, we summarize DOAC indications and contraindications and suggest the appropriate use of DOACs in common clinical scenarios, in accordance with what international guidelines and national and international health regulatory agencies recommend.