Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated mortality in the United States. Chemotherapy prolongs survival rates among patients with advanced disease, however, this is at the cost of clinically significant adverse effects. Matrine is an active component of traditional Chinese medicine and is a promising alternative drug for the treatment of NSCLC. In the present study, the therapeutic effects and the underlying molecular mechanisms of matrine on the A549 NSCLC cell line were investigated. A high concentration of matrine (1.0 mg/ml) significantly (P<0.05) inhibited cell proliferation, by 52.68±3.32%, under which cell shrinkage and disruption were observed. Flow cytometric analysis showed that the proportion of G1/G0 cells was significantly increased, whereas the proportions of S and G2/M cells were significantly decreased (P<0.05) following treatment with matrine for 48 h. These results indicated that cell arrest was induced by matrine. Upregulation of the expression of microRNA (miR)‑126, followed by downregulation of the expression of its target gene, vascular endothelial growth factor, were detected following treatment with a low concentration of matrine (0.2 mg/ml) using reverse transcription‑quantitative polymerase chain reaction analysis, immunohistochemistry and western blot analysis. In conclusion, matrine induced cell cycle arrest and apoptosis, and recovered the expression of miR‑126 in the A549 NSCLC cell line.