Objective <p>This study aimed to investigate the prognostic significance of SH3BP5-AS1 in non-small cell lung cancer (NSCLC) patients, and also to uncover its function in the progression of NSCLC.</p> Methods <p>100 NSCLC patients were recruited in this study. SH3BP5-AS1 was measured by RT-qPCR. The prognostic significance of SH3BP5-AS1 in NSCLC progression was appraised utilizing the Kaplan-Meier and Cox regression test. CCK-8 was used to detect the proliferative viability of NSCLC cells. The migratory and invasive capabilities of NSCLC cells were evaluated by Transwell assay. The interplay between SH3BP5-AS1 and miR-424-5p was verified by luciferase reporter assay and ENCORI database. The potential target genes of miR-424-5p were inspected by means of bioinformatics analysis.</p> Results <p>A reduced SH3BP5-AS1 was manifested in tissues of NSCLC patients and tumor cells. Compared with patients showing SH3BP5-AS1 low-expression, those with SH3BP5-AS1 high-expression possessed a more favorable progression-free survival time. SH3BP5-AS1 might function as an autonomous prognostic biomarker for NSCLC. Upregulation of SH3BP5-AS1 suppressed the proliferation, migration and invasion of NSCLC cells. MiR-424-5p was a downstream target miRNA of SH3BP5-AS1, and luciferase reporter assays verified that SH3BP5-AS1 and miR-424-5p interact. In NSCLC patient tissues, miR-424-5p was upregulated and it exhibited an inverse correlation with SH3BP5-AS1. Elevation of miR-424-5p neutralized the inhibitory effect of SH3BP5-AS1 overexpression on the proliferation, migration, and invasion abilities of NSCLC cells.</p> Conclusion <p>SH3BP5-AS1 is involved in NSCLC development by targeting its downstream target miRNA miR-424-5p, and it is a latent prognostic indicator for NSCLC.</p>