In the present work, response surface methodology (RSM) was coupled with computational fluid dynamics (CFD) to investigate the optimum operating parameters and hydrodynamic behavior of rectangular sheet membrane. The effect of input parameters such as pore size, feed velocity, and operating pressure on permeate flux was also evaluated to predict the optimum conditions. Limited experimental run was designed by implementing the central composite rotatable design-response surface methodology. Polynomial-regression model of second order was developed for regression analysis and analysis of variance study. The optimum conditions of pore size, operating pressure, and feed velocity were found to be 1.95 µm, 134.85 Pa, and 4.82 m/s, respectively. Pareto analysis established that the interaction of pore size-to-pore size was the most significant parameter. The quality of permeate flux was visualized using CFD-based solver. It was found that CFD-predicted pressure drops follow experimental pressure drop with high accuracy.