Thoracoscopic esophagectomy in the prone position is associated with better surgical ergonomics compared to the left lateral decubitus position due to the effects of gravity pooling blood outside the operative field and the reduced need for lung retraction. The aim of this study was to evaluate the physiological effects of prone thoracoscopic esophagectomy with single-lumen intubation on ventilation, respiratory gas exchange, and cardiovascular parameters. Thirty-two consecutive patients underwent esophagectomy either through a prone thoracoscopic approach or through a right thoracotomic approach. Samples of arterial and central venous blood, as well as ventilation and cardiovascular parameters were obtained at baseline, during induction of anesthesia, throughout the operation, and after extubation. Patients undergoing prone thoracoscopic esophagectomy showed higher oxygenation levels (p < 0.001), and a significantly lower mean pulmonary shunt fraction (p = 0.001). Perioperative hemodynamics remained stable throughout the surgical procedures. Thoracoscopic esophagectomy in the prone position with two-lung ventilation was associated with a significant improvement of global oxygen delivery and a significant reduction of the pulmonary shunt when compared to the Ivor Lewis operation.