Background To compare the efficacy and safety of aumolertinib and osimertinib in the treatment of advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Methods A retrospective analysis was performed for patients with EGFR-mutant NSCLC. The primary outcome was median progression-free survival (mPFS). Kaplan-Meier curves and the log-rank test were used to evaluate PFS and overall survival (OS), Cox regression was used for prognostic factors assessment. Results A total of 202 patients were included, comprising 106 aumolertinib users and 96 osimertinib users. In the first-line treatment, no significant difference was observed in mPFS between aumolertinib and osimertinib group (19.0 months; hazard ratio [HR], 1.15; 95% confidence interval [CI], 0.70-1.91; P = 0.58). The disease control rate (DCR) (95.7% vs. 89.8%), objective response rate (ORR) (39.1% vs. 30.6%), and median OS (27.0 vs. 38.0 months) were comparable between the two groups, with no statistical significance. In the second-line treatment, aumolertinib and osimertinib demonstrated similar mPFS (13.5 vs. 13.0 months; HR, 1.13; 95% CI, 0.75-1.71; P = 0.55), DCR (90.0% vs. 87.2%), ORR (16.7% vs. 17.0%), and median OS (24.0 vs. 20.0 months). Adverse events of grade 1-2 were also similar between the two groups. Cox regression revealed that performance status (P < 0.001) and the treatment lines of aumolertinib/osimertinib (P = 0.015) were independent prognostic factors. Conclusion Aumolertinib and osimertinib exhibit comparable efficacy and safety profiles in the treatment of EGFR-mutant NSCLC, providing a reference path for clinicians to optimize drug treatment strategies in NSCLC.