Traumatic brain injury (TBI) is a major cause of mortality and disability worldwide, with severe cases significantly increasing the risk of complications and long-term mortality. The Geriatric Trauma Outcome Score (GTOS), based on age, injury severity, and transfusion need, has been validated for predicting mortality in older trauma patients, but its utility in predicting mortality for TBI patients remains unexplored. This retrospective study included 5543 adult trauma patients with isolated moderate to severe TBI, defined by head Abbreviated Injury Scale (AIS) scores of ≥ 3, from 1998 to 2021. GTOS was calculated with the following formula: age + (Injury Severity Score × 2.5) + 22 (if transfused within 24 h). The area under the receiver operating characteristic curve (AUROC) assessed GTOS's ability to predict mortality. The optimal GTOS cutoff value was determined using Youden's index. Mortality rates were compared between high- and low-GTOS groups, separated by the optimal GTOS cutoff value, including a propensity score-matched analysis adjusting for baseline characteristics. Among 5543 patients, mortality was 8.3% (462 deaths). Higher mortality is correlated with male sex, older age, higher GTOS, and comorbidities like hypertension, coronary artery disease, and end-stage renal disease. The optimal GTOS cut-off for mortality prediction was 121.5 (AUC = 0.813). Even when the study population was matched by propensity score, patients with GTOS ≥121.5 had much higher odds of death (odds ratio 2.64, 95% confidence interval 1.93-3.61, p < 0.001) and longer hospital stays (mean 16.7 vs. 12.2 days, p < 0.001) than those with GTOS < 121.5. These findings support the idea that GTOS is a useful tool for risk stratification of in-hospital mortality in isolated moderate to severe TBI patients. However, we encourage further research to refine GTOS for better applicability in TBI patients.