BACKGROUND: Worldwide, lung cancer stands as a leading cause of mortality, with EGFR-mutated metastatic non-small cell lung cancer (NSCLC) accounting for a large percentage of cases in the Indian population. Different generations of EGFR-tyrosine kinase inhibitors (TKIs) are available to treat EGFR-mutated NSCLC. The purpose of our research was to evaluate and compare the superiority of osimertinib over gefitinib/erlotinib in terms of clinical effectiveness and safety. METHODS: A retrospective observational cohort study was conducted at the Clinical Oncology Center in the Western region of India. Patients suffering from EGFR-mutated metastatic NSCLC were recruited for the study. The response of EGFR-TKIs was assessed using objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and incidence of adverse events (AE). RESULTS: A total of 75 patients treated with EGFR TKIs were enrolled in the study. The ORR of osimertinib and gefitinib/erlotinib was 11.11% and 25.64% (p = 0.142) and DCR was found to be 69.44% and 82.05% (p = 0.28) respectively. Osimertinib and gefitinib/erlotinib had respective median PFS of 8.43 and 10.68 months. The incidence of AE of osimertinib and gefitinib/erlotinib was 1.94 and 2.49 respectively. CONCLUSION: Osimertinib was not found to be superior over gefitinib/erlotinib based on clinical effectiveness. Though it showed a better safety profile, the cost of the treatment of osimertinib over gefitinib/erlotinib was not justifiable.