Background Osimertinib is a recently approved third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR-T790M resistance mutations. The aim of the present meta-analysis was to investigate the efficacy and safety of osimertinib for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Materials and methods Databases were searched for randomized controlled studies that reported the efficacy and safety of osimertinib versus other treatments (chemotherapy, other EGFR-TKIs, etc.) in treating EGFR-mutated NSCLC. The measured effects included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), central nervous system progression-free survival (CNS-PFS), and overall survival (OS). Additional outcome was the incidence of adverse event. Relative risk (RR) for incidence and hazard ratio (HR) for survival outcomes were pooled. Results Seven studies containing 3335 participants were finally included. Osimertinib tended to improve ORR and DCR (RRs >1) as compared with other treatments. Osimertinib was also a significant protective factor for PFS, CNS-PFS, and OS (HRs p < .05). Osimertinib showed similar advantages in improving tumor response and patient survival when used as first-line, second-line, and third-line/adjuvant therapy, respectively, as compared with other treatments (RRs >1 for ORR and DCR; HRs <1 for PFS, CNS-PFS, and OS). Osimertinib also had better therapeutic effects as compared with chemotherapy, other EGFR TKIs, docetaxel + bevacizumab, and placebo, respectively. The five most common adverse events with pooled incidence > 20% were diarrhea, rash, nail effects, dry skin, and stomatitis, yet the pooled incidence of serious adverse events was less than 2%. Conclusions This meta-analysis suggests that osimertinib has a positive effect in disease control and survival for patients with EGFR-mutated NSCLC with acceptable toxicities.