Background <p>For patients with driver gene-negative non-small cell lung cancer (NSCLC) with brain metastases, chemoimmunotherapy represents the standard treatment. However, the intracranial objective response rate (iORR) remains limited, highlighting the need for effective predictive biomarkers. This study aimed to evaluate the predictive value of systemic inflammatory indices, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR). These indices were assessed for their ability to predict intracranial response and survival among these patients.</p> Methods <p>This dual-center retrospective cohort study enrolled 94 driver gene-negative NSCLC patients with brain metastases receiving first-line chemoimmunotherapy. Optimal cutoff values for NLR, PLR, and LMR for predicting iORR were determined by ROC analysis. Associations with iORR, overall survival (OS), and progression-free survival (PFS) were assessed using logistic and Cox regression.</p> Results <p>High NLR (<i>P</i> = 0.001) and high PLR (<i>P</i> = 0.001) were associated with lower iORR, while high LMR predicted higher iORR (<i>P</i> = 0.001), with an AUC of 0.774. In multivariate analysis, LMR was an independent prognostic factor for OS in the overall population (HR = 0.538, <i>P</i> = 0.032). Notably, in the subgroup receiving intracranial radiotherapy (<i>n</i> = 74), LMR retained its independent prognostic significance.</p> Conclusions <p>Pretreatment systemic inflammatory indices, particularly LMR, serve as simple and effective predictive biomarkers for intracranial response and long-term survival in driver gene-negative NSCLC patients with brain metastases treated with first-line chemoimmunotherapy. These findings provide a clinical basis for early identification of high-risk patients and may guide individualized treatment strategies.</p>