Purpose Patients with non-small cell lung cancer (NSCLC) brain metastases (BM) have poor clinical outcomes. We sought to determine if AXL-GAS6 expression can be used as independent prognostic biomarkers for NSCLC BM. Methods We retrospectively studied the medical records of 98 patients diagnosed with advanced metastatic NSCLC from December 2000 to June 2014. Out of a total of 98 patients with NSCLC metastases, 66 patients were identified to have brain metastases. The expressions of AXL and GAS6 were assessed by standard immunohistochemistry and correlated with clinicopathological factors and overall survival (OS) outcomes. Results The expression of AXL was positively associated with GAS6 expression (P < 0.001), and tumor differentiation (P = 0.014) in advanced NSCLC with metastases. AXL expression displayed no association with gender, age, smoking history, pathology, T stage, N stage, CEA, and LDH. In univariate analysis, both AXL and GAS6 were found to predict worse OS outcomes (AXL: HR 1.77, 95% CI 1.13-2.79, P = 0.01; GAS6: HR 1.80, 95% CI 1.14-2.84, P = 0.01). In the brain metastasis subgroup, the expression of AXL was positively associated with GAS6 expression (P < 0.001). Both AXL and GAS6 were found to predict worse BM-OS outcomes in univariate analysis (AXL: HR 2.19, 95% CI 1.33-4.10, P = 0.005; GAS6: HR 2.04, 95% CI 1.01-3.71, P = 0.019). In multivariate analysis, high co-expression of AXL/GAS6 was found to be an independent unfavorable risk factor for the overall study population (HR 2.33, 95% CI 1.40-3.87, P = 0.0011) and also in BM (HR 2.76, 95% CI 1.45-5.25, P = 0.001), predicting worse survival outcome. Conclusions AXL-GAS6 co-expression represents a potential independent prognostic biomarker for survival outcome in NSCLC BM patients.