The expression of long non-coding RNAs (lncRNAs) is dysregulated in non-small cell lung cancer (NSCLC). However, the functions and contributions of lncRNAs remain largely unknown. Here, we identified a critical role of long intergenic non-protein coding RNA 00858 (LINC00858) in NSCLC. Ectopic expression of LINC00858 in NSCLC cells promoted cell proliferation and induced cell migration and invasion. Moreover, LINC00858 functioned as a competitive endogenous RNA (ceRNA), effectively becoming sponge for miR-422a and thereby modulating the expression of kallikrein-related peptidase 4 (KLK4). In NSCLC patients, high expression of LINC00858 closely correlated with tumor progression. Thus, targeting the ceRNA network involving LINC00858 may be used as a treatment strategy against NSCLC.