High-end Computer Numerical Control (CNC) machine tools play an irreplaceable role in industrial production. CNC machine tools require high-speed spindle systems during the machining process, and the heat generated by the rotation of the motor and rolling bearings in the electric spindle, will cause significant thermal errors in the machine tool. To solve the temperature rise of the electric spindle, it is necessary to equip the motor and bearings with high-performance cooling water jackets. Nevertheless, traditional cooling water jackets have disadvantages in cooling performance and flow resistance. This paper presents a method of robust topology optimization (RTO) of the flow channel in cooling water jacket considering variable loading conditions. Establish a multi-physics field problem of convective heat transfer under flow-solid coupling issues. Use an interpolation method to map the design variables into the flow channel height information, which allows the three-dimensional design at the computational cost of two-dimensional topology optimization (TO), improving computational efficiency. Select a square heat exchanger as the two-dimensional numerical case, consider the variable loading conditions to optimize, and compare the differences in designs under constant and variable loading conditions. The results show that the RTO considering variable loading conditions can reduce the pressure drop of the flow channel while ensuring similar heat transfer performance. Finally, establish three-dimensional models of the traditional spiral jacket and RTO jacket to compare heat exchange performance, verifying the rationality and superiority of the RTO flow channel considering variable loading conditions.