This paper presents a fluid dynamic-based approach to the prediction of the flux decline due to partial and complete pore blocking in the microfiltration process. The electrostatic force model includes both particle–particle (PP) and particle–membrane (PM) electrostatic forces. The addition of such forces was shown to affect particle trajectories in a tortuous three-dimensional microfilter membrane geometry. The model was validated by comparing experimental flux decline data with simulation flux decline data. A design of experiments was conducted to investigate the effects of transmembrane pressure, PM- and PP-zeta potential on flux decline. The simulation experiments revealed that low flux decline was associated with relatively low transmembrane pressures and near-zero values of PP- and PM-zeta potential; and relatively high transmembrane pressures and more-negative values of PP- and PM-zeta potential. The amount of flux decline was shown to be correlated to the specific nature of partial and complete pore blocking in the pore structure.