microRNA-496 (miR-496) was found expressed abnormally in non-small cell lung cancer (NSCLC). But the study about the role of miR-496 on NSCLC was not satisfactory in date. Therefore, here we designed to explore the role of miR-496 and the probable internal mechanism in tumorigenesis of NSCLC. Increasing miR-496 both in NSCLC patients and cell lines could significantly restrained cell proliferation. For farther researching the regulation mechanism of miR-496 on NSCLC, we screen Brain derived neurotrophic factor (BDNF) as a potential target of miR-496 by bioinformatic methods and predicted a possible target of miR-496 in the 3'untranslated region (UTR) of miR-496. In clinical patients and most NSCLC cell lines including H1650, H292, H1944 and A549, increasing expression of miR-496 suppressed tumor growth via inactivating BDNF-mediated PI3K/Akt signaling pathway activation. In a word, our fingdings first represent a mechanism of miR-496 on NSCLC tumor growth via inactivating BDNF-mediated PI3K/Akt signaling pathway. (C) 2019 Elsevier Inc. All rights reserved.