Homeobox (HOX) genes encode a family of transcription factors, which play crucial roles in numerous processes, and their dysregulation is involved in the carcinogenesis of many human cancers. In the present study, we investigated the roles of HOXC8 in non-small cell lung cancer (NSCLC). We showed that HOXC8 was upregulated in clinical NSCLC specimens compared to normal lung tissues, and the high expression of HOXC8 correlated with tumor node metastasis (TNM) stage, tumor status, lymph nodal status and poor relapse-free survival for lung cancer patients. Functionally, HOXC8 expression significantly promoted the proliferation, anchorage-independent growth and migration of NSCLC, and HOXC8 functioned as a transcription activator to induce the expression of TGF beta 1, leading to an increase in the proliferation, anchorage-independent growth and migration of NSCLC. Furthermore, we demonstrated that HOXC8 expression was associated with chemoresistance and anti-apoptosis in NSCLC, suggesting that HOXC8 is a promising therapeutic target for chemosensitization of NSCLC to cisplatin. Altogether, our study defined a critical role of HOXC8 in promoting transcription of TGF beta 1 and NSCLC tumorigenesis.