<b><i>Introduction:</i></b> Existing randomised controlled trials assessing the safety and efficacy of left atrial appendage occlusion (LAAO) in atrial fibrillation (AF) were of relatively small sample size or included patients who could receive oral anticoagulant treatment after device implantation. We compared the outcomes of patients with newly diagnosed AF who received percutaneous LAAO or direct oral anticoagulant (DOAC) treatment, in a large population from a global federated health network (TriNetX). <b><i>Methods:</i></b> Patients with AF treated with percutaneous LAAO were matched with those treated with DOAC between December 1, 2010, and October 1, 2018. Outcomes were all-cause mortality, ischaemic stroke, and intracranial haemorrhage (ICH) at 5 years. <b><i>Results:</i></b> We included 200 patients with AF, who received either LAAO or DOAC. The risk of all-cause mortality, ischaemic stroke, and ICH at 5 years was not significantly different between the two groups (risk ratio [RR] for all-cause mortality: 1.52, 95% confidence interval (CI): 0.97–2.38, RR for ischaemic stroke: 1.09, 95% CI: 0.51–2.36, and RR for ICH: 1.0, 95% CI: 0.44–2.30). <b><i>Conclusion:</i></b> Patients newly diagnosed with AF, eligible for DOAC, showed similar 5-year risk of death, ischaemic stroke, and ICH when comparing those who underwent percutaneous LAAO to those receiving DOAC. Future randomised controlled trials are needed to confirm the findings and advise changes in guidelines.