The main objective of the present work is to evaluate the stochastic seismic response of a large-span continuous girder high-speed railway (CGHSR) bridge subjected to fully non-stationary seismic excitation. The stochastic ground motion is determined by a fully non-stationary ground acceleration model with both the time-varying intensity and frequency content. The stochastic seismic analysis of the large-span CGHSR bridge under a tri-directional earthquake, taking into consideration the wave passage effect, is performed using the pseudo excitation method (PEM) in frequency domain and the Monte Carlo sampling (MCS) method in time domain. A framework is proposed to determine the pseudo static displacement for the PEM under fully non-stationary seismic excitation, using the proper orthogonal decomposition (POD). A comparative study on the stochastic seismic response of the bridge is conducted using both the fully and modulated non-stationary ground acceleration. The results show that the structural nodal displacements estimated by the PEM agree well with those obtained by the MCS method. The proposed POD-based method works well in estimating the structural quasi-static displacement. Ignoring the frequency non-stationarity of the earthquake may underestimate the quasi-static displacement caused by the surface waves.