To improve the fuel economy of engineering transportation vehicles and reduce the mining costs of coal enterprises, taking the mining truck cargo box as the research object, a comprehensive lightweight design method for two working conditions is proposed. Firstly, the finite element model of the cargo box is established, and the strength performance of the cargo box under two typical working conditions, the state of running at a uniform speed with a full load and unloading are analyzed. Then, a parameterized model is established under two typical working conditions, and five design variables are defined. The sample points are selected by using the optimal Latin hypercube sampling and the corresponding response values are obtained in the established two-condition comprehensive analysis model. By comparing and verifying different approximate models, the radial basis function (RBF) approximate model is selected to establish the relationship between variables and responses. Based on the approximate model, NSGA-II algorithm is used for multi-objective optimization to obtain different optimal design schemes. The target scheme is selected for static strength and fatigue strength verification. The results show that the optimal design parameter values can be obtained by using this method and the optimized cargo box of the mine car can meet the requirements of strength under two different working conditions, as well as the weight is reduced by 7.47%.