A method used to build a prediction model for spatial evolution of the aero-optical wave front aberration caused by a supersonic mixing layer is presented. The large eddy simulation is used to visualize the instantaneous dynamical characteristics of vortices inside the flow field. The time-averaged boundary of the supersonic mixing layer is described by a piecewise function in which the two turning points are defined and expressed by a universal formula. The growth rate for supersonic mixing layers is first proposed as a function of the velocity ratio, density ratio, and compressibility of the flow field. A model for spatial evolution of aero-optical wave front aberration caused by a supersonic mixing layer is developed based on experimental data presented in the open literature and validated with numerically simulated data from two typical examples. Finally, the universality and potential application of the model built is also discussed.