Esophageal cancer surgery is still carrying a high risk of morbidity and mortality. That is why some anesthesia strategies have tried to reduce those postoperative complications. In this systematic review performed in accordance with the PRISMA-S guidelines (PROSPERO (ID: CRD42022310385)), we aimed to investigate the safety and advantages of two-lung ventilation (TLV) over one-lung ventilation (OLV) in minimally invasive esophagectomy (MIE) in the prone position. Seven trials, with a total number of 1710 patients (765 patients with TLV versus 945 patients with OLV) were included. Postoperative mortality and morbidity rates were similar between TLV and OLV when realised for esophagectomy. Interestingly, we observed no difference in changes in intraoperative respiratory parameters, operative duration, thoraco-conversion rate, number of harvested lymph nodes, postoperative heart rate and respiratory rate between TLV and OLV. TLV brings better results in terms of intraoperative oxygen arterial pressure (PaO₂) during the thoracic time, postoperative oxygenation, PaO₂ on inspired fraction of oxygen (FiO₂) ratio, duration of thoracic surgery, preoperative time, blood loss, temperature on postoperative day-1, and C-reactive protein dosage. Our study highlighted the safety of TLV for MIE in prone position when compared to OLV. Interestingly, we found better intra and postoperative ventilation parameters. The choice of ventilation modality did not influence clinical outcome after surgery and the quality of oncological resection. Large randomised controlled trials are needed to confirm these results.