Background: Endoscopic treatment of post-esophagectomy/gastrectomy anastomotic dehiscence includes Self-Expandable Metal Stents (SEMS), which have represented the “gold standard” for many years, and Endoscopic Vacuum Therapy (EVT), which was recently introduced, showing promising results. The aim of the study was to compare outcomes of SEMS and EVT in the treatment of post-esophagectomy/gastrectomy anastomotic leaks, focusing on oncologic surgery. Methods: A systematic search was performed on Pubmed and Embase, identifying studies comparing EVT versus SEMS for the treatment of leaks after upper gastro-intestinal surgery for malignant or benign pathologies. The primary outcome was the rate of successful leak closure. A meta-analysis was conducted, performing an a priori-defined subgroup analysis for the oncologic surgery group. Results: Eight retrospective studies with 357 patients were eligible. Overall, the EVT group showed a higher success rate (odd ratio [OR] 2.58, 95% CI 1.43–4.66), a lower number of devices (pooled mean difference [pmd] 4.90, 95% CI 3.08–6.71), shorter treatment duration (pmd −9.18, 95% CI −17.05–−1.32), lower short-term complication (OR 0.35, 95% CI 0.18–0.71) and mortality rates (OR 0.47, 95% CI 0.24–0.92) compared to stenting. In the oncologic surgery subgroup analysis, no differences in the success rate were found (OR 1.59, 95% CI 0.74–3.40, I² = 0%). Conclusions: Overall, EVT has been revealed to be more effective and less burdened by complications compared to stenting. In the oncologic surgery subgroup analysis, efficacy rates were similar between the two groups. Further prospective data need to define a unique management algorithm for anastomotic leaks.