Aims: Worldwide observational studies are evidencing discordance between guidelines and real‐world practice regarding direct oral anticoagulant drug (DOAC) doses. This systematic review summarizes and evaluate DOACs use in real‐world practice. Methods: This review was performed following the preferred reporting items for systematic reviews and meta‐analyses (PRISMA) guidelines searching PubMed (MEDLINE) and Medscape databases. Results: Data from 75 studies showed that most of the patients treated with DOACs for stroke prevention in atrial fibrillation received doses in accordance to the guidelines. However, a significant number of patients received off‐label doses (25–50% in most of the studies evaluated). DOAC overdosing was associated with increased all‐cause mortality and worse bleeding events while underdosing was associated with increased cardiovascular hospitalization and, particularly for apixaban, with a nearly 5‐fold increased risk of stroke. Conclusion: Patients prescribed with off‐label DOAC doses did not receive the full benefit of anticoagulation and presented an increased risk of stroke, bleeding and/or adverse effects. [ABSTRACT FROM AUTHOR]