Taking the uncertainties in the high-speed train load, environment actions, structural resistance, and material properties into consideration, the performance function of CRTS II track slab for the horizontal flexural strength is essentially a stochastic process, which may be nonstationary and non-Gaussian due to the nonnormal random variables and process. In the present paper, based on the fourth-moment transformation, a time-dependent reliability assessment method for nonstationary and non-Gaussian process is developed. In this method, the nonstationary and non-Gaussian process is firstly transformed as a standard Gaussian process, and then the time-dependent failure probability is evaluated based on the transformed Gaussian process and the cumulative distribution function of the bivariate standard normal distribution. Next, the time-dependent reliability index of the CRTS II track slab for the horizontal flexural strength is determined using the developed time-dependent reliability assessment method. The results show that the CRTS II track slab will not be damaged by the horizontal bending in the service lifetime.