Background: Non-small cell lung cancer (NSCLC) is the most common cause of brain metastases, with 10-30% of patients developing brain metastases. EGFR is a transmembrane glycoprotein that is mutated in up to 50% of NSCLCs. First-generation EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib, are limited by blood-brain barrier (BBB) penetration and exon 20 (T790M) tumor mutations. Third-generation EGFR TKIs, such as osimertinib, have shown better BBB penetration and efficacy against T790M mutations. In this retrospective study, we evaluated the overall survival (OS) and progression-free survival (PFS) in NSCLCBM patients treated with first and third-generation EGFR TKIs. Methods: NSCLCBM patients diagnosed between 2010 and 2019 at our tertiary care center were investigated. Information regarding molecular marker status, systemic therapies, and date of progression were collected. OS was defined as the start date of systemic therapy to the date of last follow-up or death. OS and PFS were estimated by the Cox proportional model. Results: A total of 193 NSCLCBM patients with an EGFR mutation were identified. 33 EGFR mutant patients received first-generation EGFR TKIs, of which 56.7% were females, 82.1% were white, and had a median age of 63.2 years. 22 patients received third-generation EGFR TKIs, 64.1% being female, 76.9% being white, and with a median age of 71.5 years. The median OS (mOS) in patients who received first and third-generation EGFR TKIs was 59.8 months and 65.9 months respectively (p-value (p) = 0.06). The median PFS (mPFS) between the first and third-generation EGFR TKI cohorts was 44.3 months and 66.9 months respectively (p= 0.048, hazard ratio (HR) = 0.50 (95% confidence interval (CI) = 0.25, 0.99). Conclusions: Newer generation of targeted therapies in NSCLCBM have focused on overcoming previous efficacy hurdles, including BBB penetration and resistant mutations. We determined that there was a significant mPFS benefit in osimertinib compared to erlotinib or gefitinib, and a trend towards significant mOS benefit in osimertinib compared to erlotinib or gefitinib in patients with NSCLCBM. However, these results should be interpreted cautiously due to treatment selection bias, and further studies need to be conducted on brain metastases lesion size and response rates.