In this study, the response surface (RS) method and forced rotordynamic analyses together with Finite-Element-Analysis (FEA) have been established to optimize the factors affecting the vibration characteristics. The spindle specification, bearings locations, cutting force, and motor-rotor unbalance mass are proposed to represent the design factors and then they are utilized to develop Machine Motorized Spindle (MMS). The FEA-based Design of Experiment (DOE) is adopted to simulate the output responses with the input factors, wherein these DOE design points are used to carry out the RS models to visualize more obvious factors affecting the dynamic characteristics of MMS. The sensitivities of these factors and their contributions to the vibration of imbalance response have been evaluated by using the RS models. The simulation results show that the motor-rotor shaft inner diameter, the distance of the back bearing location, and the rotating unbalance-mass are highly sensitive to the vibration characteristics compared to the other factors. It is found that more than two-fifths of total vibration response amplitude has been conducted by induced rotating imbalance mass. The results also showed that the proposed factors optimization method is practicable and effective in improving the vibration response characteristics.