Neonatal chylothorax is a common cause of neonatal congenital pleural effusion and is often caused by the accumulation of chylous fluid in the thoracic cavity due to the rupture of the thoracic duct and its branched lymphatic vessels for a variety of reasons. Neonatal chylothorax caused by malignant tumors is extremely rare, and this is the first case of neonatal mediastinal neuroblastoma with chylothorax in China. The boy was found to have pleural effusion in the left thoracic cavity in the uterus, and experienced apnea at birth, as well as dyspnea and cyanosis as the main manifestations after birth. He was diagnosed with left chylothorax based on conventional biochemical analysis of pleural effusion. After the treatment including persistent chest drainage and symptomatic and supportive treatment, the drainage of the left thoracic cavity reached a volume of 90-180 mL per day. Neonatal refractory chylothorax was considered. Chest radiograph on day 13 after birth showed lesions in the upper left lung field, and contrast-enhanced plain CT scan of the chest suggested the possibility of posterior mediastinal neuroblastoma. The autopsy confirmed giant posterior mediastinal neuroblastoma (poorly differentiated), which involved the C₇-T₆ spinal canal and the nearby erector spinae, with a small amount of tumor tissue in the liver and both adrenal glands. Mediastinal tumor is considered the underlying cause of chylothorax in this case.