This systematic review and meta-analysis summarized the current literature to compare the safety and efficacy between first-pass effect (FPE) and multiple-pass effect (MPE) for thrombectomy in treatment of acute ischemic stroke (AIS). Major databases were searched for studies which reported clinical outcomes regarding successful or complete recanalization after first pass of mechanical thrombectomy in AIS. The assessment of bias was performed using different scales. I2 statistic was used to evaluate heterogeneity between reviewers. Subgroup, meta-regression, and sensitivity analyses were conducted to explore the source of heterogeneity. Visualization of funnel plots was used to evaluate publication bias. A total of 9 studies were eligible for final analysis. For successful recanalization (mTICI 2b-3), favorable outcomes were seen in 49.7% (95% confidence interval (CI): 40.5-58.9%) and 34.7% (95% CI: 26.8-42.7%) of FPE and MPE patients, respectively. Mortality at 3 months was 13.8% (95% CI: 10.8-16.9%) and 26.0% (95% CI: 17.7-34.2%), respectively. For complete recanalization (mTICI 2c-3), proportion of favorable outcomes were 62.7% (95% CI: 51.2-74.2%) and 47.7% (95% CI: 37.4-58.0%) in FPE and MPE; mortality was seen in 11.5% (95% CI: 4.9-18.2%) and 17.0% (95% CI: 5.2-28.7%), respectively. For AIS with successful recanalization, FPE had more favorable outcome (odds ratio (OR): 1.85, 95% CI: 1.48-2.30; p < 0.01; I2 = 0%) and lower mortality than MPE (OR: 0.58, 95% CI: 0.42-0.79; p = 0.001; I2 = 61.9%). Similar results were seen in a subgroup analysis of patients with complete recanalization, with FPE having better outcome (OR: 1.79, 95% CI: 1.40-2.28; p < 0.01; I2 = 0%) and lower mortality risk (OR: 0.61, 95% CI: 0.44-0.86; p = 0.005; I2 = 0%) compared to MPE. FPE is associated with better outcomes than MPE after achieving successful or complete recanalization.