As the core power element of a centrifugal fan, the impeller’s structural parameters are important factors affecting the aerodynamic performance of the fan. Therefore, to improve the aerodynamic performance of centrifugal fans, in this study, we take the Powered Air-Purifying Respirator (PAPR) power system as the object of research and use a combination of computational fluid dynamics (CFD) and experimental validation to investigate the effects of the number of blades, blade inlet angle, blade outlet angle, blade height, and blade thickness on the aerodynamic performance of the fan. A five-factor, four-level orthogonal test table L16 (45) was selected to obtain the optimal combination of structural parameters for the impeller. In addition, in order to identify and visualize the features of the vortex, Q Criterion Normalized is applied to the simulation on the basis that the minimum pressure appears in the vortex core. In this study, Q Criterion Normalized is used to compare the internal vorticity of the prototype with that of the optimized prototype. The results show that (i) the order of influence of each parameter on the aerodynamic performance of the centrifugal fan is blade height > blade outlet angle > blade inlet angle > number of blades > blade thickness; (ii) the optimal combination of the structural parameters is number of blades 48, blade inlet angle 80°, blade outlet angle 120°, blade thickness 0.6 mm, and blade height 23 mm; the optimized prototype has an increase in air pressure of about 10%, an increase in air volume of about 31%, and an increase in efficiency from 49.61% to 53.57%; (iii) the intensity of internal vortices in the optimized prototype is weakened, the size of vortices and the number of vortices are reduced, and the homogeneity of the flow field is also improved.