Esophageal large-cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive malignancy that presents diagnostic and therapeutic challenges. We present the case of a 72-year-old female with LCNEC of the distal esophagus who was initially treated with chemotherapy and radiation therapy, followed by immunotherapy due to disease progression. Diagnostic imaging revealed extensive metastases to the abdominal lymph nodes. Histopathological examination confirmed the diagnosis of LCNEC with high-grade squamous intraepithelial neoplasia. The treatment complexities underscore the necessity of a multidisciplinary approach involving medical oncologists, radiation oncologists, and pathologists. While chemotherapy remains the standard, the role of immunotherapies, such as Slurilizumab in LCNEC management is evolving. Subsequent imaging revealed gradual tumor reduction, and the patient was maintained on immunotherapy. The patient has remained on immunotherapy since then, with a progression-free survival of 1 year and 4 months as of the latest follow-up, approximately 3 years post-diagnosis. This case highlights the potential of combining immunotherapy with conventional treatments for disease control. Further research is crucial to optimizing therapeutic strategies and prognostic factors for esophageal LCNEC to enhance clinical outcomes and patient care.