In order to improve therapeutic efficacy, it is a current emergency to better know the mechanisms underlying cisplatin resistance in lung cancer cells. In this study, we aim to investigate the role of Krüppel-like factor 4 (KLF4) in cisplatin-resistant lung cancer cells. We developed cisplatin-resistant lung cancer cell line A549/DDP, and then a battery of experiments was used to analyze the effects of KLF4 in cisplatin resistance of lung cancer. We found that KLF4 was significantly downregulated in cisplatin-resistant A549 cells and forced KLF4 expression inhibited cell growth and induced apoptosis. Further, we found that overexpression of KLF4 was able to inhibit cell migration and invasion, to inhibit the expression of Slug, Twist, and vimentin, and to increase the expression of E-cadherin and subsequent inhibition of the EMT process. Thus, overexpression of KLF4 may be a potential strategy for lung cancer treatment, especially for cisplatin-resistant cases.