Aims: This study aimed to evaluate the efficacy and safety of LVA-guided substrate modification catheter ablation in patients with AF. Methods: Systematic searches of the PubMed, EMBASE, and Cochrane databases were performed from inception to February 2022 for all available studies. The effect estimates were combined with the Mantel–Haenszel random-effects model. Subgroup analyses, sensitivity analysis and meta-regression were performed to explore the sources of statistical heterogeneity. Results: A total of 16 studies involving 1931 subjects (mean age: 61±10 years, 69% male) were identified. All studies included patients with paroxysmal AF, nonparoxysmal AF, or both. At a mean follow-up of 18.9 months, patients who underwent LVA ablation had significantly higher freedom from all-atrial tachycardia recurrence than patients who underwent control ablation (67.6% vs. 48.9%, risk ratios [RR] 0.66, 95% confidence interval [CI]: 0.57-0.76, P<0.001), with 34% relative risk and 18.7% absolute risk reductions in all-atrial tachycardia recurrence. Six studies assessed the incidence of stroke/transient ischemic attacks (TIAs) between the 2 groups. However, no stroke/TIA occurred in most of these studies. Furthermore, the rates of acute procedural complications were not significantly different between the 2 groups (LVA ablation 2.4% vs. control ablation 3.3%, RR 0.56, 95% CI: 0.30-1.07, P =0.08). Conclusion: LVA-guided substrate modification ablation appears to have a significant benefit in improving freedom from all-atrial tachycardia recurrence. Importantly, this benefit is achieved without a significant increase in the rates of acute procedural complications or cerebral thromboembolic events.