Fibrous-filtration media has been demonstrated with the ability to separate particulate matter in the gas. However, the complexity of involved parameters and the intricate interior structure of fibrous media pose great challenges for filter design and optimization. Herein, a novel numerical method was proposed to predict and optimize the fibrous-filtration progress by employing the computational fluid dynamic (CFD) simulation coupled with the response surface methodology (RSM). The involved filtration parameters exerted synergetic effects on filtration efficiency, which can be explained by the coupling effect of basic filtration principles with the variation of the Stk number and Pe number. Meanwhile, the pressure drop increased with the elevated solid volume fraction and airflow velocity but was not affected by the variation of particle diameters. This combined methodology of CFD simulation with RSM optimization paved a new path for the high-efficient screening of the filter design and optimization.