Primary pulmonary nuclear protein of the testis (NUT) midline carcinoma (NMC) is an extremely rare, highly aggressive thoracic malignancy that presents significant diagnostic and therapeutic challenges, characterized by heterogeneous clinical manifestations, frequent misdiagnosis, and a poor prognosis. This case report details two patients with advanced primary pulmonary NMC treated with a multimodal strategy combining anti-angiogenic agents, platinum-based chemotherapy, and radiotherapy—achieving overall survival (OS) of 32 and 13 months, respectively, which far exceeds the currently reported median OS of approximately 6.7 months for advanced NMC. A systematic literature review of 86 published cases (2011–2024) was also conducted, summarizing current diagnostic methods (such as immunohistochemistry for nuclear NUT expression and fluorescence in situ hybridization (FISH) for NUTM1 rearrangement) and treatment modalities for NMC. Findings indicate that multimodal therapy incorporating anti-angiogenic agents yields superior clinical outcomes compared to conventional monotherapy, especially for patients ineligible for surgery. The report also highlights diagnostic pitfalls, such as overlapping histopathological features with squamous cell carcinoma, and underscores how integrating anti-angiogenic therapy addresses the aggressive biology of NMC, offering a new therapeutic direction for this refractory malignancy.