RATIONALE: Non-small cell lung cancer (NSCLC) that co-expresses thyroid transcription factor-1 (TTF-1) and p40 represents a distinct subtype of lung cancer. This case report details a 53-year-old male patient with NSCLC exhibiting co-expression of TTF-1 and p40, highlighting the need for further investigation into this unique presentation of NSCLC. PATIENT CONCERNS: A 53-year-old male, nonsmoker, presented to our hospital in November 2023 with complaints of cough, expectoration, chest pain, and dyspnea. DIAGNOSES: Computed tomography scans revealed perihilar lesions in the upper lobe of the right lung with distal obstructive pneumonia, invasion into adjacent mediastinal structures, multiple pulmonary metastases, possible mediastinal and right hilar lymph node metastases, pleural effusion, and a slightly thickened pleura in the right lung, along with multiple metastatic lesions in the liver. Immunohistochemical analysis showed positive staining for CK (AE1/AE3), TTF-1, and p40, while CK56, CD68, CD45 (LCA), D2-40, and Ki-67 (50%+) were negative, leading to the diagnosis of lung adenocarcinoma. Second-generation sequencing identified mutations in ERBB2 (EXON20.p.Y772-A775dup) and TP53 (EXON5.c.404G-Tp.C135F). INTERVENTIONS: The patient underwent 6 cycles of chemotherapy with a regimen consisting of bevacizumab, pemetrexed, and carboplatin. OUTCOMES: Posttreatment evaluations on December 28, 2023, and February 25, 2024, indicated stable disease. The patient is currently on a maintenance chemotherapy regimen of bevacizumab and pemetrexed, and his condition is stable. LESSONS: The co-expression of TTF-1 and p40 in NSCLC may define a novel subtype of lung cancer. Further research is imperative to elucidate its characteristics, molecular mechanisms, and to establish its morphological features and therapeutic strategies.