ABSTRACT Background Left atrial appendage occlusion (LAAO) has emerged as a non‐pharmacological alternative to oral anticoagulation (OAC) for stroke prevention in patients with atrial fibrillation (AF). Following the publication of recent CHAMPION‐AF and CLOSURE‐AF trials, an updated synthesis of evidence is warranted to clarify the long‐term comparative efficacy and safety of LAAO versus OAC in patients with AF. Methods We conducted a systematic review and meta‐analysis of randomized controlled trials (RCTs) comparing LAAO with OAC in adults with AF. A comprehensive search of major databases was performed from inception to April 2026. The primary efficacy outcomes were major adverse cardiovascular events (MACE) and stroke. The primary safety outcome was non–procedure‐related bleeding. Random‐effects models were used to calculate pooled risk ratios (RRs) with 95% confidence intervals (CIs). Results Six RCTs including 7,004 patients (3,681 LAAO; 3,323 OAC) were analyzed. No statistically significant difference was observed for MACE (7.5% vs 6.9%; RR 1.03, 95% CI 0.79‐1.34) or stroke (3.7% vs 3.2%; RR 1.07, 95% CI 0.80‐1.43). LAAO was associated with a significantly lower risk of non‐procedure‐related bleeding (9.8% vs 16.7%; RR 0.63, 95% CI 0.52‐0.77), corresponding to an absolute risk reduction of 6.9% and an approximate number needed to treat of 15 based on crude pooled event rates over the observed trial follow‐up. Trial sequential analysis indicated that the accumulated evidence for MACE and stroke remained inconclusive. Comparator‐type subgroup analyses showed no significant interaction for MACE ( p = 0.67) or stroke ( p = 0.81) between contemporary predominantly‐DOAC and VKA comparator trials. Conclusions LAAO was associated with lower non‐procedure‐related bleeding, while no statistically significant differences were observed for MACE or stroke. The available efficacy evidence remains inconclusive regarding equivalence or non‐inferiority, and larger trials are needed. These findings support individualized consideration of LAAO when the long‐term bleeding burden of anticoagulation is clinically important.