ObjectiveThe aim of this study was to explore the mechanism behind lncRNA small nucleolar RNA host gene 19 (lncRNA SNHG19)/microrNA-299-5P (miR-299-5p)/mitogen-activated protein kinase 6 (MAPK6) signaling axis promoting metastasis of non-small cell lung cancer (NSCLC).MethodsTo analyze the abnormal expression of lncRNAs in NSCLC, 50 surgically resected NSCLC and adjacent tissue samples were collected from August 2021 to August 2022. The mRNA expression levels of lncRNA SNHG19, Mir-299-5p, and MAPK6 were detected by qRT-PCR. The functions of lncRNA SNHG19, Mir-299-5p and MAPK6 were investigated by CCK-8, clone formation, EdU, scratch, Transwell western blotting (WB) and in vivo xenograft assay. RNA fluorescence in-situ hybridization (FISH), RNA pull-down, dual luciferase reporter, and RNA co-immunoprecipitation assays were used to explore the mechanism of action between lncRNA SNHG19, miR-299-5p, and MAPK6.ResultsHigh expression of lncRNA SNHG19 was correlated with poor prognosis, tumor size, lymph node metastasis, and TNM stage in NSCLC patients (P < 0.05). Cell function experiments showed that lncRNA SNHG19 could improve the proliferation, clone formation, migration, and invasion ability of A549 cells both in vitro and in vivo (all P < 0.05) and increased the relative expression levels of vimentin and MAPK6 (P <0.05). The relative expression level of E-cadherin was decreased (P < 0.05). lncRNA SNHG19 can interact with Mir-299-5p and regulate the expression level of MAPK6.ConclusionlncRNA SNHG19 is upregulated in NSCLC tissues and cells, and its high expression is associated with tumor progression and poor survival. Moreover, it can act as a molecular sponge for Mir-299-5p to regulate MAPK6 expression and promote the proliferation and metastasis of A549 cells.