Purpose <p>Brain metastases (BM) cause substantial morbidity and mortality in patients with non-small cell lung cancer (NSCLC). Updated epidemiological studies are crucial to guide screening and treatment strategies. We investigated the prevalence, timing, and outcomes of BM in patients diagnosed with NSCLC utilizing the TrinetX Oncology database.</p> Methods <p>Data from patients with histologically confirmed NSCLC were extracted from the TrinetX Oncology database. Precocious, synchronous, and metachronous BM were defined as BM diagnosed before, within 2 months, and after 2 months of the NSCLC diagnosis, respectively. Clinical variables were compared between patients with and without BM using Chi-squared and t-tests. Kaplan-Meier and Cox regression analyses were used to evaluate overall survival (OS), after propensity-score matching for age at diagnosis of NSCLC, sex, stage at diagnosis, extracranial metastases, and cancer-directed therapy.</p> Results <p>Among 25,714 patients with NSCLC, 18.9% had BM (3.1% precocious, 6.5% synchronous, and 9.3% metachronous). The median time to BM was 7.7 months in patients with initial stage IV NSCLC. Patients with BM received significantly higher rates of cancer-directed therapies compared to those without BM. Patients with BM (with or without extracranial metastases) had reduced OS compared to patients with extracranial metastases only (HR[95%CI] = 1.2[1.1–1.3]). Synchronous BM were associated with lower OS than metachronous BM after the diagnosis of NSCLC (HR[95%CI] = 1.8[1.6-2.0]), but not after BM diagnosis.</p> Conclusion <p>BM impact outcomes of patients with NSCLC causing significant morbidity and mortality. Our findings highlight the importance of early detection and targeted interventions in NSCLC patients at risk of BM.</p>