SummaryWith the launch of the high‐speed train project in California, the seismic risk is a crucial concern to the stakeholders. To investigate the seismic behavior of future California High‐Speed Rail (CHSR) bridge structures, a 3D nonlinear finite‐element model of a CHSR prototype bridge is developed. Soil‐structure and track‐structure interactions are accounted for in this comprehensive numerical model used to simulate the seismic response of the bridge and track system. This paper focuses on examining potential benefits and possible drawbacks of the a priori promising application of seismic isolation in CHSR bridges. Nonlinear time history analyses are performed for this prototype bridge subjected to two bidirectional horizontal historical earthquake ground motions each scaled to two different seismic hazard levels. The effect of seismic isolation on the seismic performance of the bridge is investigated through a detailed comparison of the seismic response of the bridge with and without seismic isolation. It is found that seismic isolation significantly reduces the deck acceleration and the force demand in the bridge substructure (i.e., piers and foundations), especially for high‐intensity earthquakes. However, seismic isolation increases the deck displacement (relative to the pile cap) and the stresses in the rails. These findings imply that seismic isolation can be promisingly applied to CHSR bridges with due consideration of balancing its beneficial and detrimental effects through using appropriate isolators design. The optimum seismic isolator properties can be sought by solving a performance‐based optimum seismic design problem using the nonlinear finite‐element model presented herein. Copyright © 2016 John Wiley & Sons, Ltd.