Abstract Background and purpose EGFR TKIs alone have demonstrated activity against intracranial disease in EGFR mutant non-small cell lung cancer (NSCLC). This study aimed to determine if upfront cranial radiotherapy improves intracranial disease control and survival outcomes in EGFR mutant NSCLC with brain metastases relative to TKIs alone. Materials and methods We searched MEDLINE and various conference proceedings from 2008 to July 2014 for eligible studies where patients received upfront cranial radiotherapy or TKIs alone. Outcomes of interest were overall intracranial disease response rate (ORR), four-month intracranial disease progression-free survival (PFS), two-year overall survival (OS) and neurological adverse events (AE). We used random effects models to pool outcomes across studies and compared them using interaction tests. Results We found 12 non-comparative observational studies ( n = 363) with severe methodological limitations. Upfront cranial radiotherapy results in similar intracranial disease ORR (relative risk (RR) 0.93, 95% confidence interval (CI) 0.82–1.06; interaction p value ( p ) = 0.53), improved four-month intracranial disease PFS (RR 1.06, 95% CI 1.00–1.12; p = 0.03), improved two-year OS (RR 1.33, 95% CI 1.00–1.77; p = 0.05) but caused more neurological AEs than TKIs alone. Conclusion There is evidence, albeit of low quality, that upfront cranial radiotherapy may improve intracranial disease control and survival outcomes compared with TKI alone.