In order to study the running safety and derailment mechanism of high-speed railway under earthquake, a full-size vehicle-track model shaking table test was carried out by using a 6 m×6 m large-scale shaking table. Based on the shaking table test, a similar multi-freedom and multi-rigid-body vehicle-track numerical model was established, and the test results were compared with the calculation results. The two results were basically consistent, indicating the validity of the numerical calculation model. Then, according to the safety reserve of derailment coefficient and other indicators between the normal running state and the earthquake state of the train, a new idea for determining the earthquake early warning threshold of high-speed railway was proposed. On the basis of the vehicle-track numerical model, time-lapse analysis was carried out by inputting 6 different horizontal seismic waves. The relationship between the derailment coefficient, the wheel load reduction rate, and the peak acceleration of seismic wave was analyzed. Finally, the warning thresholds corresponding to different derailment coefficient limits and different wheel load reduction rate limits were given, and it was suggested that the earthquake warning threshold of China’s high-speed railway should be set to 40 gal.