The incidence and mortality rate of nonsmall cell lung cancer (NSCLC) are continuously increasing. Recently, the important roles of long noncoding ribonucleic acid (lncRNA) zinc finger antisense1 (ZFAS1) in the development of many disease have been proved. However, the roles of ZFAS1 in NSCLC are still not completely understood. Thus, this study aimed to explore the potential roles and underlying mechanisms of lncRNA ZFAS1 in the progression of NSCLC. Our results demonstrated that lncRNA ZFAS1 expression was significantly upregulated in NSCLC tissues and cell lines. Loss-of-function experiments revealed that lncRNA ZFAS1 inhibition could remarkably suppress NSCLC cells proliferation in vitro. Bioinformatic analysis and luciferase reporter assay revealed that lncRNA ZFAS1 directly interacted with miR-590-3p. Rescue experiments showed that miR-590-3p inhibitor reversed the cell proliferation function of lncRNA ZFAS1 knockdown in vitro. Furthermore, we confirmed that lncRNA ZFAS1 inhibited cell division cycle 42 (Cdc42) expression by regulating of miR-590-3p in NSCLC cells. Therefore, our study indicates that lncRNA ZFAS1/miR-590-3p axis is involved in NSCLC cell proliferation. It also suggests that lncRNA ZFAS1 is a putative tumor oncogene in NSCLC.