<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Aims</jats:title> <jats:p>We conducted a systematic review and meta-analysis on three outcomes. We assessed the efficacy and safety of direct oral anticoagulants (DOAC) compared to vitamin K antagonists (VKA) in morbidly obese patients with atrial fibrillation (AF). We compared the efficacy and safety of DOAC in obese patients and non-obese patients with AF. Finally, we updated the current knowledge of outcomes of AF patients with obesity compared with normal-weight patients regardless of anticoagulation type.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and results</jats:title> <jats:p>Using PubMed and Embase, we searched for literature published from inception to August 2020 for studies conducted in morbidly obese patients with AF who used DOACs and/or VKA for stroke or systemic embolism (stroke/SE) prevention that report efficacy and/or safety data. GRADE assessment was performed to determine the quality of the meta-analysis results. Direct oral anticoagulant was not statistically different from VKA in reducing stroke/SE with relative risk (RR) of 0.85 [95% confidence interval (CI): 0.56–1.29; very low certainty evidence]. Major bleeding risk was lower in the DOAC groups with RR of 0.62 (95% CI: 0.48–0.80; low certainty evidence). Obese patients with AF who used DOACs had lower risk of stroke/SE and similar major bleeding risk compared to non-obese patients with RR of 0.77 (95% CI: 0.70–0.84; low certainty evidence) and 1.02 (95% CI: 0.94–1.09; low certainty evidence), respectively. Obese patients with AF who used any type of anticoagulant had lower risk of stroke/SE compared to normal-weight patients with RR of 0.62 (95% CI: 0.57–0.69; low certainty evidence).</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>The use of DOACs in morbidly obese patients may be reasonable if needed, and more dedicated studies are needed to make a more robust recommendation.</jats:p> </jats:sec>