Malignant pleural mesothelioma is a rare neoplasm that mostly occurs in elderly men. Recurrent unilateral pleural effusion is the most typical presentation and it is very rare to find extra-thoracic lymphadenopathy before the primary tumor, even in advanced cases. Herein, we report a challenging case of a young man presenting with unresolved fever, sore throat, and dysphagia associated with massive pleural effusion, cardiac tamponade, and multiple cervical lymphadenopathy with mesothelial cells infiltration. Microscopic examination of lymph node structures revealed reactive follicular architecture and massive infiltration of epithelioid cells with pleomorphic vesicular nuclei in the sinuses and subcapsular spaces. Immunohistochemical staining of the epithelioid cells demonstrated a positive reaction to PAN-Cytokeratin (CK), CK7, calretinin, Wilms tumor (WT1), and CK5/6 while Ki-67 labeling index showed low proliferative activity. Biopsy of pericardium and fluid cytology revealed no evidence of malignancy. The patient underwent a second surgery due to unresolved effusion. Sample taken from the anterior mediastinal area showed infiltrating tubulo-glandular proliferation spreading to mediastinal fat component. Thereafter, the diagnosis of malignant mesothelioma originating from mediastinal reflections of the pleura was established. It is very important for the pathologist to accurately diagnose malignant mesothelioma over other differential diagnoses to prevent misdiagnosis in such rare and complicated cases.