Abstract: High-clearance self-propelled sprayers have been widely used in modern agriculture in recent years, due to the operating speed, ground clearance, and tank capacity. It is very necessary to equip the suspension system with a better vibration-damping effect. Once the sprayer is operating under complex conditions, a faster driving speed is required by the sprayer suspension to fully dissipate the vibration energy that is transferred from the ground to the body for better comfort and smoothness. Ground friendliness (i.e., without the excessive dynamic tire load) can cause soil compaction and damage during spraying. The tilt and pitch movement of the vehicle can trigger the sloshing impact of the liquid in the tank under the excitation of a complex road surface. The spring-loaded mass of the vehicle and the height of the center of mass can be used to balance the change of liquid filling conditions during spraying in the suspension system under the best matching parameters. It is difficult to guarantee the smoothness of the whole vehicle, due to the liquid sloshing in the tank and the time-varying quality for the complex working conditions of a high clearance self-propelled sprayer. In this study, the equivalent mechanical model of the liquid sloshing in the tank was constructed using the dynamic characteristics of the liquid shaking and the mechanical model equivalence criterion. The model parameters were selected, according to the mechanical model equivalence criterion. The equivalent model was fused to establish a seven-degree-of-freedom nonlinear vertical dynamics model of the chassis, considering the liquid sloshing factor. A theoretical model was provided to realize the operation of the multi-objective optimization for the suspension system parameters. The following simplifications were made when modeling the whole vehicle. There was no cushioning mechanism between the liquid tank and the body, which was regarded as a rigid connection. The center of the body tilting and pitching motion coincided with the center of the bottom of the tank. The liquid in the tank was shaken in the form of a tipping force and moment acting on the body. A genetic algorithm (GA) was used to optimize the four variable parameters of front and rear suspension stiffness and damping. The GA tool in Matlab Optimization, and the Sim function were used to realize the operation of the Simulink dynamics simulation model and the invocation of the simulation. The optimal parameter matrices of suspension stiffness and damping were obtained for different road surfaces and fluid-filled conditions after optimization. The results show that the suspension stiffness parameter was significantly reduced, compared with the initial. By contrast, the suspension damping parameter slightly increased relative to the initial value. The optimal stiffness and damping values increased with the increase of the liquid filling ratio of the drug tank. At the same time, the optimal optimization of the vehicle body vertical acceleration, lateral tilt angle speed, pitch angle speed and dynamic wheel load under the optimal parameters reached 27.5%, 16.4%, 25.8%, and 17.6%, respectively. The optimization of vehicle vertical acceleration and pitch angle velocity gradually decreased with the increase of the liquid filling ratio, while the best optimization effect of dynamic wheel load and lateral tilt angle velocity appeared at a liquid filling ratio of 0.5 and 0.6, respectively. In addition, there was also a different optimization effect in the two operating conditions of the sprayer, in which the dynamic wheel load in the transit transport condition was often lower than that of the spraying operation under each liquid filling condition. The other three groups of variables were mostly better in transit. A complete spraying machine test platform was built to carry out the complete spraying machine tests. The test also used the acceleration and angle sensors. A typical working condition was used to measure the body acceleration, each suspension unsprung mass acceleration, body pitch angle velocity, and lateral tilt angle velocity. Four sets of replicated experiments were conducted with the road conditions and suspension parameter conditions as experimental variables. The test results show that the vertical acceleration of the sprayer's spring-loaded mass was much smaller than that of the unsprung mass, due to the vibration-damping effect of the suspension. Once the suspension was adjusted to the optimal parameters, the body vertical acceleration was reduced by 15.58% and 18.72% under the two road conditions, and the body roll/pitch angular velocity was reduced by more than 10%. The findings can provide a strong reference for the design, parameter optimization, and control of chassis suspension in tank-type vehicles.