Background and AimObesity affects nearly 650 million adults worldwide, and the prevalence is steadily rising. This condition has significant adverse effects on cardiovascular health, increasing the risk of hypertension, coronary artery disease, heart failure, and atrial fibrillation (AF). While anticoagulation for obese patients with AF is a well‐established therapy for the prevention of thromboembolism, the safety and efficacy of different anticoagulants in this specific population are not well explored. This meta‐analysis aimed to compare direct oral anticoagulants (DOAC) to vitamin K antagonists in obese populations with AF.MethodsThe PRISMA guidelines were followed for this meta‐analysis, registered in PROSPERO (CRD42023392711). PubMed, PubMed Central, Embase, Cochrane Library, and Scopus databases were searched for relevant articles from inception through January 2023. Two independent authors screened titles and abstracts, followed by a full‐text review in Covidence. Data were extracted in Microsoft Excel and analyzed using RevMan v5.4 using odds ratio as an effect measure.ResultsTwo thousand two hundred fifty‐nine studies were identified from the database search, and 18 were included in the analysis. There were statistically significant reductions in the odds of ischemic and hemorrhagic stroke in the DOAC group compared with the VKA group (OR 0.70, CI 0.66–0.75) and (OR 0.47, CI 0.35–0.62), respectively. In addition, the DOAC group exhibited lower odds of systemic embolism (OR 0.67, CI 0.54–0.83), major bleeding (OR 0.62, CI 0.54–0.72), and composite outcome (OR 0.72, CI 0.63–0.81).ConclusionBased on the findings from this meta‐analysis, DOACs demonstrate superior safety and efficacy in obese patients with AF compared with VKAs. These results may have significant implications for guiding anticoagulation strategies in this patient population.