The bearing-spindle system functions as the critical rotary support component in precision machine tools. During the machining process, the local temperature increases and thermal deformation of the components in the bearing-spindle system results in alterations to the contact load distribution, friction heat generation, and heat transfer characteristics of the system. This may subsequently lead to localized temperature anomalies within the spindle system, an increase in the thermal deformation of the shafting, and a reduction in machining accuracy. This paper investigates the thermal deformation of the spindle system and the characteristics of thermoelastic interactions between shafting components. It considers the operating environment of the spindle system (including preload, assembly tolerance, temperature, and speed, among others) as design variables, while employing the axial thermal deformation of the spindle, shaft temperature difference rate, transient preload fluctuation rate, and transient extreme value of assembly tolerance as objective functions and constraint conditions. A design variable and target variable experimental sample space is established based on the transient thermal network model of the shafting system. Based on the constructed experimental sample space, the quadratic response surface methodology is employed to develop a fitting equation that accounts for the transient thermoelastic behavior of the design parameters in the bearing-spindle system. Subsequently, a generalized mathematical model for the optimization design of assembly parameters in the precision spindle system is established. By optimizing the shafting assembly parameters, this study provides a valuable reference for enhancing the thermal performance and assembly quality of the spindle during the design phase.