Aiming at the problem that the current hydrocyclone separator is affected by multiple structural parameters and there is interaction between the multiple structural parameters, it is difficult to determine the optimal structure. Taking the new axial inlet hydrocyclone separator as the research object, a fast parametric optimization method based on response surface optimization method is proposed. The overflow outlet diameter, overflow tube depth and small cone length, which have significant influence on the separation efficiency of the axial inlet hydrocyclone separator, are selected as the optimal variables, and the cyclone separation efficiency is selected as the response index. A mathematical driving model between the response index and the optimal variables is constructed by using the second-order polynomial basis function. The optimal structural parameters of the new axial inlet hydrocyclone separator are obtained through the response optimization of the parameter variables in the global response range through the mathematical driving model, and the numerical simulation method and laboratory test are double verified. The results demonstrated that the axial inlet hydrocyclone achieved the highest separation efficiency within the studied operational parameter range when the overflow pipe diameter was 6mm, the overflow pipe depth was 20mm, and the small cone length was 60mm. The separation efficiency improved from 89% to 93%. The rapid optimization of the structural parameters of the axial inlet hydrocyclone was successfully accomplished using the response surface optimization method.