In order to investigate the derailment mechanism and safety operation area of high-speed trains under earthquake, a coupled vehicle-track dynamic model considering earthquake effect is developed, in which the vehicle is modeled as a 35 degrees of freedom (DOF) multibody system with nonlinear suspension characteristic and the slab track is modeled as a discrete elastic support model. The rails of the track are assumed to be Timoshenko beams supported by discrete rail fasteners, and the slabs are modeled with solid finite elements. The system motion equations are solved by means of an explicit integration method in time domain. The present work analyzes in detail the effect of earthquake characteristics on the dynamical behaviors of a vehicle-track coupling system and the transient derailment criteria. The considered derailment criteria include the ratio of the wheel/rail lateral force to the vertical force, the wheel loading reduction, the wheel/rail contact point traces on the wheel tread, and the wheel rise with respect to the rail top, respectively. The present work also finds the safety operation area, the derailment area, and the warning area of high-speed trains under earthquake, and their boundaries. These areas consist of three key parameters influencing the dynamical behavior of high-speed train and track under earthquake. The three key influencing parameters are, respectively, the vehicle speed and the lateral and vertical peak ground acceleration (PGA) of an earthquake. The results obtained indicate that the lateral earthquake motion has a greater influence on the vehicle dynamic behavior and its running safety compared to the vertical earthquake motion. The risk of derailment increases quickly with the increasing of lateral earthquake motion amplitude. The lateral earthquake motion is dominant in the vehicle running safety influenced by an earthquake. While the vertical earthquake motion promotes jumping of the wheels easily, not easy is flange climb derailment. And the effect of the vehicle speed is not significant under earthquake.