BACKGROUND: The genomic landscape of non-small cell lung cancer (NSCLC) in the Indian patients remains underexplored. We revealed distinctive genomic alterations of Indian NSCLC patients, thereby providing vital molecular insights for implementation of precision therapies. METHODS: We analyzed the genomic profiles of 325 lung adenocarcinoma and 81 lung squamous carcinoma samples from Indian patients using targeted sequencing of 50 cancer related genes. Correlations between genomic alterations and clinical characteristics were computed using statistical analyses. Additionally, we identified distinct features of Indian NSCLC genomes by comparison across different ethnicities. RESULTS: Our genomic analysis revealed several noticeable features of Indian NSCLC patients. Alterations in EGFR (45.8%), TP53 (27.4%), ALK (11.4%) and KRAS (10.2%) were predominant in adenocarcinoma, with 68% eligible for targeted therapies. Squamous carcinoma exhibited prevalent alterations in TP53 (40.7%), PIK3CA (17.3%), and CDKN2A (8.6%). We observed higher frequency of EGFR alterations (18.5%) in lung squamous carcinoma patients, significantly distinct from other ethnicities reported till date. Beyond established correlations, we observed 60% of PD-L1 negative squamous patients harbored TP53 alterations, suggesting intriguing therapeutic implications. CONCLUSIONS: Our data revealed unique genomic variations of adenocarcinoma and squamous carcinoma patients, with significant indications for precision medicine and clinical practice of lung cancers. The study emphasizes the importance of clinical utility of NGS for routine diagnostics.