Abstract Traumatic brain injury (TBI) is a significant healthcare concern in several countries, accounting for a major burden of morbidity, mortality, disability, and socioeconomic losses. Although conventional prognostic models for patients with TBI have been validated, their performance has been limited. Therefore, we aimed to construct machine learning (ML) models to predict the clinical outcomes in adult patients with isolated TBI in Asian countries. The Pan-Asian Trauma Outcome Study registry was used in this study, and the data were prospectively collected from January 1, 2015, to December 31, 2020. Among a total of 6540 patients (≥ 15 years) with isolated moderate and severe TBI, 3276 (50.1%) patients were randomly included with stratification by outcomes and subgrouping variables for model evaluation, and 3264 (49.9%) patients were included for model training and validation. Logistic regression was considered as a baseline, and ML models were constructed and evaluated using the area under the precision-recall curve (AUPRC) as the primary outcome metric, area under the receiver operating characteristic curve (AUROC), and precision at fixed levels of recall. The contribution of the variables to the model prediction was measured using the SHapley Additive exPlanations (SHAP) method. The ML models outperformed logistic regression in predicting the in-hospital mortality. Among the tested models, the gradient-boosted decision tree showed the best performance (AUPRC, 0.746 [0.700-0.789]; AUROC, 0.940 [0.929-0.952]). The most powerful contributors to model prediction were the Glasgow Coma Scale, O2 saturation, transfusion, systolic and diastolic blood pressure, body temperature, and age. Our study suggests that ML techniques might perform better than conventional multi-variate models in predicting the outcomes among adult patients with isolated moderate and severe TBI.