Background: Despite improved surgical techniques and perioperative management, anastomotic leakage (AL) after esophageal cancer surgery remains a potential complication. In most cases, spontaneous healing upon proper drainage is observed, but sometimes, AL results in intractable enterocutaneous fistulas. We here report a case of intractable enterocutaneous fistula caused by post-esophagectomy AL and successfully treated by scopolamine ointment and negative pressure wound therapy (NPWT). Case presentation: A 77-year-old man underwent thoracoscopic subtotal esophagectomy with 3-field lymph node dissection, followed by gastric tube reconstruction through the posterior mediastinal route. On the 6th postoperative day, AL was identified, forming an enterocutaneous fistula. Initially, conservative treatment was performed, but the fistula failed to close. We hypothesized that the substantial amount of exudate might be hampering fistula closure. Scopolamine ointment was used to reduce the amount of fluid. NPWT was also initiated to promote wound healing. Approximately 3 weeks after the beginning of the treatment, the fistula closed; oral intake became possible, and the patient was discharged from the hospital without any symptoms. Conclusions: The combination of scopolamine ointment and NPWT may be regarded as one effective treatment option for intractable enterocutaneous fistula due to AL after esophagectomy.