Spindle box is an indispensable part of the spindle system, and its thermal error is one of the important factors affecting the machining accuracy of CNC machine tools. The multi-objective optimization design and research of the spindle box were carried out based on thermal design by combining Taguchi method and finite element method. The thermal characteristics experiment platform of the spindle system was built. The vertical CNC milling machine of a machine tool factory was taken as the research object, and the temperature data of its spindle system was obtained. According to the experimental data, 9 groups of the spindle box optimization models were established. 9 groups of models with temperaturestructure field coupling were simulated and analyzed by using the finite element method, and the temperature distribution cloud map and thermal deformation distribution cloud map of each model were obtained. The optimized results of spindle box structure and the optimal combination of primary and secondary factors were obtained. The results show that the factors influencing the thermal deformation of the spindle box from high to low are length L of the bottom plate, distance B, width A of the floor plate and distance C,while the factors influencing the quality of the spindle box from high to low are length L of the bottom plate, distance B, distance C and width A of the floor plate. The study provides a reference for reducing the research and development cost of CNC machine tools.