Abstract Background Molecular and genetic alterations of non-small-cell lung cancer (NSCLC) now play a vital role in patient care of this neoplasm. The authors focused on the impact of epidermal growth factor receptor mutation (EGFR-mt) status on the survival of patients after brain metastases (BMs) from NSCLC. The purpose of the study was to understand the most desirable management of BMs from NSCLC. Methods This was a retrospective observational study analyzing 647 patients with NSCLC, including 266 patients with BMs, diagnosed at our institute between January 2008 and December 2015. EGFR mutation status, overall survival (OS) following diagnosis, OS following BMs, duration from diagnosis to BMs, and other factors related to OS and survival after BMs were measured. Results Among 647 patients, 252 (38.8%) had EGFR mutations. The rate and frequency of developing BMs were higher in EGFR-mt patients compared with EGFR wildtype (EGFR-wt) patients. EGFR-mt patients showed longer median OS (22 vs 11 months, P < .001) and a higher frequency of BMs. Univariate and multivariate analyses revealed that good performance status, presence of EGFR-mt, single BM, and receiving local therapies were significantly associated with favorable prognosis following BM diagnosis. Single metastasis, compared with multiple metastases, exhibited a positive impact on patient survival after BMs in EGFR-mt patients, but not in EGFR-wt NSCLC patients. Conclusions Single BM with EGFR-mt performed better than other groups. Furthermore, effective local therapies were recommended to achieve better outcomes.