Analysis of the seismic response of high CFRDs under non-uniform ground motion input is conducted using a novel non-uniform input motion calculation method combined with nonlinear FEM. The non-uniform input motion calculation method and its basic assumption are validated. The response of CFRDs under uniform and non-uniform input is compared to discuss the necessity of conducting seismic analysis of high CFRDs under realistic non-uniform ground motion input. When the acceleration at the surface of the free field for dynamic simulations with uniform and non-uniform input is kept consistent, the seismic response of CFRDs under non-uniform input is in general significantly smaller, while the dynamic tensile stress around the edges of the concrete face slab is greater. The simulation results suggest that non-uniformity of the ground motion input has important effects on the seismic response of high CFRDs and should be considered in the seismic design of CFRDs. The influence of the incident angle of seismic waves is also investigated, with results indicating that the influence is waveform dependent, while being frequency independent.