The aim of this paper is to investigate the derailment of a tilting railway vehicle on curved tracks that are experiencing the twin effects of rail irregularities and an earthquake. The nonlinear governing differential equations of motion for a tilting railway vehicle are derived using a heuristic nonlinear creep model and Kalker’s linear theory. The tilting vehicle is modeled as a 24-degree-of-freedom system, with the lateral, roll and yaw motions of each wheelset, as well as the lateral, vertical, roll and yaw motions of the bogie frames and the car body all taken into account. The derailment quotients and offload factors of a tilting railway vehicle experiencing the twin effects of an earthquake on its wheelsets, bogie frames and car body in the lateral direction, and rail irregularities acting on its wheelsets in the lateral direction are investigated at various tilt angles. The obtained results show that, in general, a derailment quotient and an offload factor evaluated with an earthquake taken into consideration are larger than those obtained without consideration of the earthquake. Moreover, the derailment quotient and offload factor of a wheelset increase with an increase in the tilt angle of the railway vehicle experiencing excitations from an earthquake and also rail irregularities. Finally, the effects of suspension parameters on the derailment quotient and offload factor of a wheelset are investigated. Taken together, it is clear that the influences of rail irregularities and an earthquake on the derailment of a tilting railway vehicle cannot be disregarded.