Lung cancer remains one of the most common cancer-associated mortalities worldwide, and platinum-based doublet chemotherapies are recommended as the first‑line treatment for advanced non‑small cell lung cancer (NSCLC). However, the frequent development of multidrug resistance, to cisplatin regimens in particular, is a major cause of chemotherapy failure in patients with aggressive NSCLC. Wnt/β‑catenin signaling and sex‑determining region Y box 2 (Sox2) have been implicated in the development and progression and resistance to epidermal growth factor receptor‑targeting therapy in lung cancer. The present study aimed to explore the effects of Wnt/β‑catenin and Sox2 signaling on the chemoresistance of cisplatin‑resistant lung cancer cells by assessing the effects of Sox2 on Wnt/β‑catenin signaling activity, cell migration, invasion and clonogenicity, and susceptibility to cisplatin in lung adenocarcinoma A549 cells and cisplatin-resistant A549/DDP cells. The results demonstrated that an enforced expression of Sox2 led to inhibition of Wnt/β-catenin signaling activity, potentially by upregulating glycogen synthase kinase 3 β in A549 and A549/DDP cells. An overexpression of Sox2 promoted cell migration and invasion, in addition to enhancing the clonogenic capacity in A549 cells. Notably, knockdown Sox2 using short hairpin RNA led to an enhanced susceptibility of A549 and A549/DDP cells to cisplatin, along with increased cell apoptosis. The present study thus suggests that Sox2 may be an important regulator in development of chemoresistance of lung cancer cells and may be a novel therapeutic target for treatment chemoresistant lung cancer.