LncRNAs play a crucial role in regulating the progression of NSCLC, making them potential targets for cancer diagnosis and treatment. Therefore, identifying new lncRNAs as therapeutic target and comprehending their underlying regulatory mechanisms are crucial for treating NSCLC. In this study, we found that glioblastoma down-regulated RNA (GLIDR) was increased in non-response NSCLC patients with the primary treatment, and GLIDR was also highly expressed in NSCLC patients. We used bioinformatic analysis and luciferase assays to identify that microRNA-342-5p (miR-342-5p) directly targets GLIDR. MiR-342-5p overexpression inhibits NSCLC cell proliferation, migration, and invasion, whereas miR-342-5p inhibition promotes NSCLC malignancy, which can be rescued by suppressing GLIDR. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PPARGC1A) was identified as a downstream target of miR-342-5p. PPARGC1A inhibition significantly suppresses NSCLC malignancy, whereas overexpression promotes it. The results also revealed that GLIDR overexpression reduced PPARGC1A inhibition by miR-342-5p, and increased PPARGC1A expression reversed the inhibition of NSCLC malignancies caused by decreased GLIDR. To the best of our knowledge, we are the first to discover that GLIDR promotes NSCLC progression by sponging miR-342-5p to regulate PPARGC1A expression, presenting that GLIDR act as a potential therapeutic target in NSCLC. Overall design: To investigate the abnormality expressed lncRNA in NSCLC, we performed a whole-transcriptome sequencing compared lncRNA expression in the normal lung epithelium cell line (HEB) and the lung adenocarcinoma cell line (A549). Then the differentially expressed genes (DEGs) were analyzed using data obtained from the RNA sequencing.