Abstract: Objective To analyze the role of the targeted therapeutic drug osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), in elderly patients with advanced non-small cell lung cancer (NSCLC), and to explore the effects of this regimen on tumor markers and T lymphocyte subsets. Methods A total of 102 eldly advanced NSCLC patients who diagnosed at Baoji Hospital Affiliated to Xian Medical University from June 2020 to June 2023 were enrolled. The patients were randomly divided into two groups according to the treatment protocol. The control group (n=51) received a albumin-bound paclitaxel combined with cisplatin chemotherapy regimen, while the observation group (n=51) received the osimertinib regimen. The observed indicators and comparison items included objective response rate (ORR) and disease control rate (DCR), serum tumor marker levels, T lymphocyte subgroups, and quality of life before and after treatment. Additionally, the occurrence of adverse reactions between the two groups was compared. Results Compared with control group, the ORR (49.02% vs 29.41%, χ²=4.113, P=0.043) and DCR (70.59% vs 49.02%, χ²=4.935,P=0.026) of the observation group were higher, and the incidence of adverse reactions was lower ［5.88% (3/51) vs 21.57% (11/51), χ²=5.299,P=0.021］. After treatment, the observation group had lower levels of cytokeratin 19 fragments, carcinoembryonic antigen, carbohydrate antigen 125, cytoskeleton-associated protein 4, and quality of life scores (P＜0.05). The T lymphocyte subgroups (excluding CD8+) were significantly higher than the control group (P＜0.05). Conclusion The EGFR-TKI targeted therapy drug osimertinib is effective in treating elderly advanced NSCLC patients with EGFR mutation and/or T 790M mutation compared to traditional chemotherapy regimens. It can lower tumor marker levels, improve the immune status of the body, and has a lower incidence of adverse reactions. Osimertinib can improve the quality of life while ensuring medication safety.