Nowadays, reliable and accurate prediction of the seismic response of high-speed railway bridges and then rapid assessment of their seismic fragility is crucial for the risk assessment of regional high-speed railway bridges. However, the traditional seismic fragility assessment based on nonlinear time history analysis (NTHA) has a characteristic of high computational cost. Therefore, this study explores different machine learning (ML) methods to develop a reliable rapid seismic fragility assessment framework for high-speed railway bridges. Taking a typical high-speed railway continuous (HRC) bridge as a case, a large number of numerical model and ground motion pairs considering various structural and ground motion features are established. Then, the two types of models including six popular ML methods are investigated, in which Lasso regression, artificial neural network (ANN) and support vector machine (SVM) are single models, and random forest (RF), extreme gradient boosting (XGBoost) and light gradient boosting machine (Light GBM) are ensemble models. A database containing a large number of seismic responses of different components is established through the NTHA to develop prediction models, and the optimal hyperparameters of different ML models are determined by ten-fold cross-validation and grid search. The study results show that the ensemble model can reliably predict the seismic response of the HRC bridge compared with the single model, and the XGBoost model is recommended for seismic fragility assessment. On this basis, the optimal ML model obtained by the performance evaluation is applied to develop seismic fragility curves of the HRC bridge, which are compared with the fragility curves based on NTHA. The results indicate that the XGBoost model can effectively replace the traditional NTHA for rapid seismic fragility assessment of the HRC bridge, which can achieve a sufficient assessment level while saving calculation costs.