Migration and invasion is one of the most important features in tumor metastasis and development. Non-small cell lung cancer (NSCLC) is one of the most common types of cancer globally, and has been linked to air contamination. Evidence indicates that cysteine-rich angiogenic inducer 61 (CYR61) is associated with the migration and invasion of NSCLC. Overexpression of CYR61 protein promotes the migration and the transition of tumor-derived vascular endothelial cells in NSCLC. However, the association between CYR61 and NSCLC remains poorly understood. Lenvatinib is an oral multi-target drug that targets various receptors upon tumor angiogenesis. Dexamethasone is widely approved for combination therapy in patients with NSCLC. In the current study, the expression and function of CYR61 in NSCLC was analyzed during the progression of NSCLC. Inhibitory effects on migration and invasion induced by lenvatinib and dexamethasone were determined by migratory and invasion assays. Migratory pathways of extracellular signal-regulated kinases (ERK) and protein kinase B (AKT) were also investigated by targeting vascular endothelial growth factor (VEGF) and CYR61 via synergistic treatment with transforming growth factor-β1 (TGF-β1) and dexamethasone. Therapeutic outcomes of combined treatment with lenvatinib and dexamethasone were assessed in NSCLC-bearing mice. The results of the present study indicate that cooperative treatment of lenvatinib and dexamethasone significantly inhibited TGF-β1-induced cell migration and suppressed tumor growth (P<0.01). Notably, the results demonstrated that dexamethasone eradicated the promotion effects of TGF-β1 on the AKT/epithelial-mesenchymal transition process and lenvatinib extinguished tumor cell metastasis by targeting VEGF. The results of the current study also demonstrate that dexamethasone suppressed the expression of CAG-I and enhanced expression of matrix metalloproteinase-1. Synergistic treatment for NSCLC was demonstrated to be efficacious. In conclusion, dexamethasone inhibited AKT/ERK phosphorylation and lenvatinib antagonism bound VEGF leading to the limitation of migration and invasion of cancer cells in NSCLC.