Background Due to their poor natural history and lack in level-I evidence, patients with large vessel occlusion and large core infarcts (Alberta Stroke Program Early Computed Tomographic Score <6) have been excluded from receiving mechanical thrombectomy. This systematic review and meta-analysis seeks to summarize current evidence from published randomized controlled trials to compare the safety and efficacy of mechanical thrombectomy with optimal medical therapy in treating stroke patients with large core infarcts. Methods We searched PubMed and EMBASE for randomized controlled trials investigating the safety and efficacy of mechanical thrombectomy vs optimal medical therapy in patients presenting with large vessel occlusion and large infarcts. Basic demographic and comorbidities were assessed, and clinical outcomes were compared, including modified Rankin scale 0–3, and 0–2 at 3 months, symptomatic intracranial hemorrhage, decompressive hemicortectomy, and 90-day mortality. Results Three randomized controlled trials totaling 1011 patients (501 and 510 in the medical management and mechanical thrombectomy arm, respectively) were included. Patients undergoing mechanical thrombectomy had significantly higher odds of achieving better functional outcomes at 3 months: Modified Rankin scale 0–2 (OR = 3.05, 95% CI = 2.101–4.4021, p < 0.0001) and modified Rankin scale 0–3 (OR = 2.20, 95% CI = 1.67–2.89, p < 0.0001) as compared to those receiving optimal medical management. There were no differences between groups in 90-day mortality (OR = 0.93, 95% CI = 0.70–1.23, p = 0.60), symptomatic intracranial hemorrhage (OR = 1.89, 95% = CI 0.95–3.77, p = 0.07) or decompressive hemicraniectomy (OR = 1.25, 95% CI = 0.69–2.25, p = 0.46). Conclusion Mechanical thrombectomy for patients with large infarcts is associated with improved functional outcomes and a similar safety profile compared to optimal medical management. Ongoing trials will help better refine the target population that benefits the most from treatment.