Background: Percutaneous left atrial appendage occlusion (LAAO) is an established nonpharmacologic strategy for stroke prevention in atrial fibrillation (AF). Its comparative effectiveness and safety relative to contemporary medical therapy, including direct oral anticoagulants (DOACs), remain uncertain following recent large randomized controlled trials (RCTs). Methods: We performed a systematic review and meta-analysis of RCTs comparing catheter-based LAAO with medical therapy in AF patients. PubMed, CENTRAL, and ScienceDirect were searched from inception through May 2026. Dichotomous outcomes were pooled as risk ratios (RRs) with 95% confidence intervals (CIs) using random-effects models. The primary outcome was the composite primary endpoint. Secondary outcomes included all-cause death, cardiovascular death, all stroke/TIA, ischemic stroke/TIA, systemic embolism, major bleeding, and nonprocedural major bleeding. Risk of bias was assessed using ROB 2. Results: Six RCTs were included, contributing 7073 participants (3729 LAAO; 3344 medical therapy). LAAO was not associated with significant differences in the composite endpoint (RR 1.02; 95% CI 0.85–1.23), all-cause death (RR 1.02; 95% CI 0.79–1.31), cardiovascular death (RR 0.93; 95% CI 0.67–1.29), all stroke/TIA (RR 1.06; 95% CI 0.81–1.38), ischemic stroke/TIA (RR 1.24; 95% CI 0.88–1.76), systemic embolism (RR 0.76; 95% CI 0.12–4.77), or total major bleeding (RR 0.93; 95% CI 0.77–1.13). LAAO significantly reduced nonprocedural bleeding (RR 0.54; 95% CI 0.46–0.63; p < 0.0001; I² = 0.0%). Heterogeneity was low to moderate across outcomes. Conclusions: No significant differences were observed between LAAO and medical therapy for the composite endpoint, mortality, or thromboembolic outcomes; however, confidence intervals for ischemic stroke/TIA and systemic embolism remained wide and cannot exclude a clinically meaningful excess of thromboembolic events after LAAO. LAAO was associated with a substantial and consistent reduction in nonprocedural bleeding. These findings suggest LAAO may be considered an individualized alternative to oral anticoagulation for selected patients with high bleeding risk or anticoagulation intolerance, weighing upfront procedural risk against this bleeding benefit, while uncertainty for rare thromboembolic outcomes remains to be resolved.