With a high mortality rate, non-small cell lung cancer (NSCLC) is a major challenge for patients and clinicians. The high cost and side effects of chemo-drugs severely influence disease outcome. With advantages of action prolongation and solitary target for embedded drugs, liposomal nanoparticle-based modification was investigated in this study with valeric acid, aimed at exploring its impacts and value on NSCLC. The efficacy comparisons of chemo-drugs (cisplatin, paclitaxel and liposomal nanoparticle-modified valeric acid) were conducted utilizing human NSCLC cell lines, normal lung fibroblasts, pulmonary epithelial cell line, and mouse tumor models. Additionally, the underlying therapeutic mechanisms for this novel liposomal nanoparticle in NSCLC were also explored via analysis of protein changes in tumor tissues. Results showed that, in comparison with conventional chemotherapeutics (cisplatin and paclitaxel), novel liposomal nanoparticle-modified valeric acid effectively retarded the growth of human NSCLC cell lines to a greater extent, and even successfully restrained further progression of tumor tissues in vivo. Furthermore, this novel liposomal nanoparticle-modified valeric acid exhibited lower cytotoxicity towards normal lung cell lines. Additionally, the anti-cancer function of this novel liposomal nanoparticle-modified valeric acid was found to be related to STAT3/Cyclin D1 pathway. The current study confirmed that, compared with cisplatin and paclitaxel, this novel liposomal nanoparticle-modified valeric acid displayed significant therapeutic effect on NSCLC, with lower cytotoxicity to normal cells. It has therefore further promoted research progress and significance on NSCLC research in the clinical management of NSCLC.