Background: Postoperative leakage after esophagectomy is associated with significant life-threatening complications. Recently, endoscopic vacuum therapy (EVT) was introduced and has been successfully used as a new treatment option. The purpose of this study was to evaluate the safety and efficacy of EVT for the management of postoperative leakage after esophagectomy. Methods: A total of 22 patients were treated with either intraluminal or intracavitary EVT for the management of postoperative leakage from May 2012 to April 2018. The location of leakage was intrathoracic in 17 patients and cervical in five patients. The outcomes of EVT were analyzed retrospectively. Results: Complete postoperative leakage closure was achieved in 19 of 22 patients. The median duration of EVT application was 14 days (range 2–103), and a median number of three EVT systems (range 1–14) were used. In 19 patients who were successfully managed with EVT, oral feeding was possible a median of 15 days after the first day of treatment. There were no cases of mortality related to postoperative leakage. Conclusions: EVT is a well-tolerated and effective therapeutic option for the treatment of various types of postoperative leakage after esophagectomy.