BACKGROUND: Resveratrol, a natural polyphenolic phytoalexin, has potent anti-tumor activity. Recently, it was found to induce autophagy in cancer cells. However, the effects of resveratrol on autophagy in non-small-cell lung cancer (NSCLC) cells have not yet been clearly elucidated. MATERIALS AND METHODS: A549 and H1299 cells were treated with different concentrations of resveratrol. Cell growth and apoptosis were measured by CCK-8 assay and flow cytometry, respectively. A549 cells were then treated with 200 μM resveratrol or SRT1720. Cell autophagy was detected by western blot and immunofluorescence. RESULTS: In this study, we found that resveratrol exerted the anti-tumor effect through inhibiting cell proliferation and promoting cell apoptosis in NSCLC cells dose-dependently. Resveratrol has also increased the relative expression of Beclin1 and LC3 II/I while decreased p62 expression, suggesting that resveratrol induced autophagy in NSCLC cells. In addition, resveratrol increased SIRT1 expression and SIRT1 activator SRT1720-induced autophagy of NSCLC cells. SIRT1 knockdown reduced resveratrol-induced autophagy significantly. These results indicated that resveratrol might induce autophagy through upregulating SIRT1 expression. Moreover, inhibiting autophagy by autophagy inhibitor 3-methyladenine or SIRT1 inhibitor nicotinamide significantly suppressed proliferation while promoted apoptosis compared with the resveratrol 200 μM group, suggesting that resveratrol-induced autophagy might act as a protective mechanism to promote NSCLC cell survival and inhibiting autophagy can enhance the anti-tumor effect of resveratrol. Besides that, resveratrol treatment inhibited Akt/mTOR while p38-MAPK was activated in NSCLC cells in a dose-dependent manner. Activating Akt/ mTOR pathway by IGF-1 or inhibiting p-38-MAPK pathway by doramapimod significantly inhibited cell proliferation while increased cell apoptosis of NSCLC cells compared with the resveratrol 200 μM group. CONCLUSION: Taken together, our findings suggest that resveratrol inhibited proliferation but induced apoptosis and autophagy via inhibiting Akt/mTOR and activating p38-MAPK pathway. Resveratrol-induced autophagy might act as a protective mechanism to promote NSCLC cell survival. Therefore, inhibition of autophagy may enhance the anti-tumor activity of resveratrol in NSCLC.