<p>Post-earthquake operational performance design is regarded as an essential component in seismic design for high-speed railway bridges, with the primary difficulty lying in the proposal of a design procedure that takes into consideration both seismic and structural variability. In this study, response spectra of post-earthquake operational performance index for high-speed railways considering seismic and structural variability were established based on natural vibration periods and beam-end deformations, respectively. The controlled structural vibration periods and beam-end deformations for bridges were derived, and the performance design methodology based on the controlled indices was proposed. The research results indicate that the constructed target seismic-induced track alignment irregularity is not significantly affected by the selected ground motion records and possesses satisfactory stability. The post-earthquake operational performance spectra calculated based on the target seismic irregularity and equivalent structural assumption have good applicability to random earthquakes and structures. For random bridges with known parameters such as bearing stiffness and pier height, the pier cross-sectional dimensions and reinforcement ratio scheme can be determined through the proposed method, achieving integrated conventional seismic design and post-earthquake operational performance design for high-speed railway bridges.</p>