Abstract Background Esophagomediastinal fistula caused by intrathoracic esophageal cancer perforation poses significant challenges in treatment. We present a case of such a patient successfully treated by achieving complete resolution through surgical resection following chemotherapy with 5-FU, cisplatin, and pembrolizumab. Methods Clinical and surgical findings of the patient were reviewed through chart analysis. A 46-year-old male presented to the emergency room with fever and cough. Computed tomography (CT) indicated esophageal-mediastinal fistula due to mid-thoracic esophageal cancer and perforation. Endoscopic examination revealed a 5cm circumferential mass 20cm from the upper incisors, along with perforation. Biopsy confirmed poorly differentiated squamous cell carcinoma, with a PD-L1 CPS score of 80. The patient received multidisciplinary treatment involving chemotherapy followed by planned surgical intervention. Results First of all, the patient underwent peroral endoscopic gastrostomy for dietary intake. After 3-weeks interval three cycles of 5-FU (800mg/BSA, Day1-5), cisplatin (80mg/BSA, Day1), and pembrolizumab (200mg, Day1), complete resolution of the abscess cavity and significant reduction in esophageal cancer lesions were observed. Robotic transthoracic esophagectomy and Mckeown operation were performed, achieving complete resection of the esophagus including the primary lesion. Pathological examination revealed complete remission of the primary lesion and absence of metastatic nodes among the 51 dissected lymph nodes. After subsequent additional three cycles of anticancer-immunotherapy combined therapy were done, no signs of recurrence were found on CT scan performed 3 months post-surgery. Conclusion We report a case of successful treatment of a patient with thoracic esophageal cancer complicated by difficult-to-treat esophago-mediastinal fistula, managed effectively with concurrent chemotherapy and surgical intervention.