To adapt to the rapid growth of the logistics market and further improve the competitiveness of railway transportation, the high-speed freight train with a design speed of 350 km/h is being developed in China. The safety of the train under great axle load of 17 t and dynamic load is unknown. This paper is aimed to study the running safety of the high-speed freight train coupled with various cargo loading conditions negotiating a sharp curve at high velocity. A numerical model integrated a fluid-structure coupled container model and the nonlinear high-speed freight train was set up by the software of LS-DYNA. The fluid-structure interaction model between the container and fluid cargo was established using the Arbitrary Lagrangian-Eulerian (ALE) method. Two influencing parameters, including the cargo state in the container and the fill level, were selected. The study results showed that the wheelset unloading ratio and overturning coefficient could be significantly affected by the liquid sloshing, while the influence of sloshing on the risk of derailment was slight. In general, increasing the cargo filling rate would contribute to vehicle operation safety. In conclusion, this study would provide theoretical help for the running safety of the newly designed high-speed freight train.