Background: Genomic instability (GI) is an effective prognostic marker of cancer. Thus, in this work, we aimed to explore the impact of GI derived signature on prognosis in non-small cell lung cancer (NSCLC) patients using bioinformatics methods. Methods: The data of NSCLC patients were collected from The Cancer Genome Atlas. Totally 1794 immune related genes were downloaded from immport database. The optimal prognosis related genes were identified by univariate and LASSO Cox analyses. The risk score model was built to predict the NSCLC patients' prognosis. The immune cell infiltration was analyzed in CIBERSORT. Results: The 951 differentially expressed genes (DEGs) between the genomic stability (GS) and GI groups were enriched in 862 Gene ontology terms and 32 Kyoto Encyclopedia of Genes and Genomes pathways. Based on the 13 optimal genes, a prognostic risk score mode for NSCLC was established, and the high-risk patients exhibited worse overall survival. Moreover, the nomogram could reliably predict the clinical outcomes. The immune cell infiltration and checkpoints were significantly differential between the two groups (high-risk and low-risk). Conclusion: The GI related 13-gene signature (TMPRSS11E, TNNC2, HLF, FOXM1, PKMYT1, TCN1, RGS20, SYT8, CD1B, LY6K, MFSD4A, KLRG2 APCDD1L) could reliably predict the prognosis of NSCLC patients.