Polysaccharides from Glehnia littoralis (PGL), a genus in the Apiaceae family, are commonly used in Chinese medicine and have anti-cancer properties. Nevertheless, our present understanding of the specific processes behind such impacts is inadequate. MicroRNAs (miRNAs) and long noncoding RNAs have been reported to regulate lung cancer tumorigenicity. The current study sought to evaluate the role of MALAT1, miR-145, and the effects of PGL in non-small-cell lung cancer (NSCLC), as well as the underlying processes. A lung cancer cell line (A549) and a bronchial epithelial cell line (BEAS-2B) were utilized in the current study. Quantitative real-time PCR, luciferase reporter assay, MTT assay, transwell migration assay, apoptosis assay, and western blot were applied to assess the effects of MALAT1/miR-145 axis on anticancer activates of PGL in NSCLC. We found that MALAT1 was up-regulated in lung cancer cell lines, while miR-145 was down-regulated. Furthermore, MALAT1 may act as a competitive endogenous RNA (ceRNA) by directly sponging miR-145, which further regulating the SOX9 expression. PGL treatment decreased the cell viability, in addition to down-regulating MALAT1 in A549 NSCLC cells. SiRNA-knockdown of MALAT1 could enhance the effects of PGL on NSCLC cell viability, apoptosis, and migration. PGL treatment also reduced SOX9 and EMT-related protein levels. Besides, MALAT1 knockdown enhanced the effects of PGL on SOX9 and EMT genes expression. Collectively, these findings indicate a novel MALAT1/miR-145/SOX9 pathway for NSCLC progression. Knockdown of MALAT1 could increase the cytotoxicity of PGL in lung cancer by regulating the miR-145/SOX9 Axis. Our study could shed light on the development of therapeutic strategies for lung carcinoma treatment.