background: Y-box binding protein 1 (YBX1) is a common oncogene in non-small-cell lung cancer (NSCLC), which is regulated by microRNAs (miRNAs) and transcription factors. This research aims to explore the function of YBX1, miR-148a-3p and Runt-related transcription factor 3 (Runx3) in NSCLC development, and analyze their interactions. methods: YBX1, miR-148a-3p and Runx3 levels were detected using quantitative reverse transcription polymerase chain reaction(RT-PCR), Western blotting or immunohistochemical staining. The functions of YBX1, miR-148a-3p and Runx3 were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing, transwell, flow cytometry, xenograft model and Western blotting analyses. The binding correlation was validated through dual-luciferase reporter analysis and chromatin immunoprecipitation (ChIP). results: YBX1 expression was upregulated, and miR-148a-3p and Runx3 levels were reduced in NSCLC samples and cell lines. YBX1 silence restrained NSCLC cell proliferation, migration, invasion and tumor growth, and enhanced apoptosis. YBX1 was targeted via miR-148a-3p. MiR-148a-3p knockdown promoted cell proliferation, migration, invasion and tumor growth, and repressed apoptosis, and these effects were abolished by YBX1 silence. Runx3 upregulation restrained cell proliferation, migration, invasion and tumor growth, and facilitated apoptosis. Runx3 bound with miR-148a-3p promotor to regulate miR-148a-3p expression. Runx3 silence modulated YBX1 expression though miR-148a-3p to promote NSCLC progression by increasing Cyclin D1, Cyclin B1, Slug-1, MMP-2 and MMP-9 levels. conclusions: Runx3-miR-148a-3p axis targeted YBX1 to modulate NSCLC progression.