A 13-year-old neutered male lion was presented with a primary neoplasm arising from the left mandibular salivary gland associated with metastases to regional lymph nodes, thoracic viscera (lungs, heart, esophagus, and diaphragm), and kidney. Histologic and immunohistochemical investigations led to a diagnosis of a high-grade mucoepidermoid carcinoma of the mandibular salivary gland. In this case report, we point out the importance of the immunohistochemical characterization for differential diagnosis between various types of carcinomas of the salivary gland.