Background Direct mechanical thrombectomy may result in similar outcomes compared to a bridging approach with intravenous thrombolysis (IVT + MT) in acute ischemic stroke. Recent randomized controlled trials have varied in their design and noninferiority margin. Aim We sought to meta-analyze accumulated trial data to assess the difference and non-inferiority in clinical and procedural outcomes between direct mechanical thrombectomy and bridging therapy. Summary of review We conducted a systematic review of electronic databases following the preferred reporting items for systematic reviews and meta-analyses guidelines. Random effects meta-analyses were conducted for the pooled data. The primary outcome was good functional outcome at 90 days (modified Rankin scale (mRS) ≤ 2). Secondary outcomes included excellent functional outcome (mRS ≤ 1), mortality, any intracranial hemorrhage, symptomatic intracranial hemorrhage, successful reperfusion (thrombolysis in cerebral infarction ≥ 2 b), and procedure-related complications. Four randomized controlled trials comprising 1633 patients (817 direct mechanical thrombectomy, 816 bridging therapy) were included. There were no statistical differences for the 90-day good functional outcome (OR = 1.02, 95% CI 0.84–1.25, p = 0.54, I² = 0%), and the absolute risk difference was 1% (95% CI: −4% to 5%). The lower 95% CI falls within the strictest noninferiority margin of −10% among included randomized control trials. Direct mechanical thrombectomy reduced the odds of successful reperfusion (OR = 0.76, 95% CI: 0.60–0.97, p = 0.03, I² = 0%) and any intracranial hemorrhage (OR = 0.65, 95% CI: 0.49–0.86, p = 0.003, I² = 38%). There was no difference in the remaining secondary outcomes. The risk of bias for all studies was low. Conclusion The combined trial data assessing direct mechanical thrombectomy versus bridging therapy showed no difference in improving good functional outcome. The wide noninferiority thresholds set by individual trials are in contrast with the clinical consensus on minimally important differences. However, our pooled analysis indicates noninferiority of direct mechanical thrombectomy with a 4% margin of confidence. The application of these findings is limited to patients presenting directly to mechanical thrombectomy-capable centers and real-world workflow times may differ against those achieved in a trial setting.