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Background Brainstem glioma (BSG) is a rare neoplasm characterized by short survival and high mortality. Thus far, treatment efficacy for this tumor has remained limited, highlighting the critical demand for novel and effective therapeutic strategies. The utilization of CyberKnife Stereotactic Radiation Therapy(CyberKnife-SRT) for BSG may render favorable outcomes. Nevertheless, robust clinical data remain limited at present. Therefore, this study was designed to assess the efficacy and safety of CyberKnife-SRT in the treatment of BSG. Methods A retrospective analysis was conducted using clinical data from patients treated with CyberKnife-SRT for BSG between August 2009 and July 2024. Demographic characteristics and treatment parameters were extracted. Overall Survival (OS) was defined as the interval from initial diagnosis to death from any cause or the last follow-up; survival curves were estimated with the Kaplan–Meier method, and inter-group differences were evaluated using the Log-rank (Mantel-Cox) test. Univariate Cox proportional-hazards models were fitted to assess the association between each candidate variable and the risk of death. Subsequently, variables were selected by backward stepwise elimination based on Akaike’s information criterion (AIC), and a multivariate Cox proportional-hazards model was constructed to identify factors independently associated with mortality. And the incidence of adverse reactions of the patients were analyzed. Results A total of 54 BSG patients treated with CyberKnife-SRT were enrolled, with a median follow-up of 71 months (Range: 3.03 - 182.97 months). Median Overall Survival (mOS) for the entire cohort was 20.9 months (95% CI 15.7 - 67.6). Median Progression-free Survival (mPFS) was 13.7 months(95% CI 8.83 - 20.08). The 1-year and 5-year OS rates were 83.39% and 32.74%, respectively. The 1-year and 5-year PFS rates were 57.02% and 21.36%. Univariate Cox regression analysis revealed that tumor volume > 8 cm³ (HR 3.04, 95% CI 1.61 - 7.97, p = 0.024), age 3–17 years (HR 2.27, 95% CI 1.04 - 4.96, p = 0.039), and age 51–69 years (HR 5.47, 95% CI 1.76 - 17.02, p = 0.003) were significantly associated with an increased risk of death, whereas Karnofsky Performance Status (KPS) score ≥ 70 was the only protective factor identified (HR 0.39, 95% CI 0.19 - 0.82, p = 0.013), while surgery, chemotherapy and targeted therapy had no significant impact. Multivariate Cox regression analysis showed that, compared with the 18–50-year age group, the 51 - 69-year age group had a significantly higher risk of death (HR = 6.69, 95% CI 2.03-22.00, p = 0.002). Regarding safety, 17 (31.48%) patients developed radiation-induced brain edema, and 4 (7.41%) patients had obstructive hydrocephalus. All conditions improved after active treatment. No radiation necrosis or radiotherapy-related deaths were observed. Conclusions Indirect comparison with historically reported data indicates that CyberKnife-SRT is associated with prolonged survival in patients with BSG, with manageable treatment-related toxicities. These results suggest a favorable benefit-risk profile for CyberKnife-SRT in this patient population.