BACKGROUND: Venous thromboembolism (VTE) is a life-threatening complication commonly occurring after acute ischemic stroke (AIS), with an increased risk of mortality. Traditional risk assessment tools lack precision in predicting VTE in AIS patients due to the omission of stroke-specific factors. METHODS: We developed a machine learning model using clinical data from patients with acute ischemic stroke (AIS) admitted between December 2021 and December 2023. Predictive models were developed using machine learning algorithms, including Gradient Boosting Machine (GBM), Random Forest (RF), and Logistic Regression (LR). Feature selection involved stepwise logistic regression and LASSO, with SHapley Additive exPlanations (SHAP) used to enhance model interpretability. Model performance was evaluated using area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: Among the 1,632 AIS patients analyzed, 4.17% developed VTE. The GBM model achieved the highest predictive accuracy with an AUC of 0.923, outperforming other models such as Random Forest and Logistic Regression. The model demonstrated strong sensitivity (90.83%) and specificity (93.83%) in identifying high-risk patients. SHAP analysis revealed that key predictors of VTE risk included elevated D-dimer levels, premorbid mRS, and large vessel occlusion, offering clinicians valuable insights for personalized treatment decisions. CONCLUSION: This study provides an accurate and interpretable method to predict VTE risk in patients with AIS using the GBM model, potentially improving early detection rates and reducing morbidity. Further validation is needed to assess its broader clinical applicability.