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. This review was performed following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines searching PubMed (MEDLINE) and Medscape databases. 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. 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.