Many classic components or equipment in the fields of aerospace, robotics, and civil engineering, can be classified into a flexible structure with moving components actively traveling on it, which constitutes a self-excited system and exhibits complex nonlinear dynamic coupling effects between the flexible substrate and moving mass. The excited structural vibration due to moving mass motion will bring challenges to the stability and mission effectiveness of the whole system, especially in the case of short-time and fast movement. Thereby, the paper presents analyses and optimization of the motion profiles of a moving mass traveling on a flexible simply supported beam with the goal of reducing the self-excited structural deflection and vibration. The dynamic responses imply that the moving mass would induce evident motion-induced dynamic deflection and residual vibration, and such effects highly depend on the motion profile. A high-efficiency motion planning approach is imposed by employing the quintic spline curve and Kriging surrogate model based optimization algorithm combined with the expected improvement infilling-sampling criterion. The favorable motion profiles can be found by using only 2 waypoints and approximately 100 samplings. In the case of minimization of the transient deflection amplitude, lower transient deflection, which is even lower than the static value, can be obtained using the optimized motion profile. In the case of minimization of residual vibration energy, a smooth deformation history of the substrate beam can be produced while the vibration energy has also been significantly reduced. Using the minimization of residual vibration energy as an objective function is recommended as a preferable way in the motion planning issue. Improved motion profiles with shorter terminal time are obtained and proved the effectiveness and robustness of the proposed optimization approach. The proposed approach and associated results could provide a feasible way to design a favorable moving mass motion from the perspective of vibration reduction for flexible structures.