BACKGROUND: Histone deacetylase (HDAC) inhibition offers the potential for anti-cancer effects in a variety of cancers, since HDAC plays an important role in cancer development and progression. Thus, we demonstrated the therapeutic efficacy of the new HDAC inhibitor, CG-745, in comparison with existing HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA) in non-small lung cancer (NSCLC) cells. METHODS: The effect of CG-745 on apoptosis and reactive oxygen species (ROS) dependent mitochondrial dysfunction in human A549 and H460 cells was investigated by Annexin V assay, MitoSoX and Western blot. Also, to confirm HDAC expression, it was analyzed using real-time PCR. To confirm the inhibitory effect of EMT on CG-745 by TGF-β1, Western blot, scratch analysis, and matrigel invasion analysis were performed. RESULTS: Compared to SAHA, CG-745 inhibited cell viability and mRNA expression of HDACs such as HDAC1, HDAC2, HDAC3 and HDAC8. It also caused apoptosis, ROS and mitochondrial dysfunction in a concentration-dependent manner. CG-745 reversed EMT induced by TGF-β1 in A549 and H460 cells, and inhibited migration and invasion increased by TGF-β1. CG-745 has been shown to inhibit EMT and induce apoptosis in NSCLC cells. CONCLUSION: It suggests that CG-745 could be a new treatment strategy for treatment of NSCLC.