Herein response surface methodology (RSM) is employed to optimize the fabrication of polyethersulfone (PES) nanofiltration (NF) membranes via phase inversion. The Box–Behnken design matrix is applied to develop predictive regression models, minimize the number of experiments, and investigate the effects of parameters on the response. Four important parameters, including PES polymer concentration (18–22% w/w), PVP concentration (0–2% w/w), evaporation time (0–3 min) and coagulation bath temperature (0–50 °C), were chosen as independent variables and the optimization objectives were water flux and rejection. Consequently, 27 experiments were conducted to construct a quadratic model. The fabricated NF membranes were characterized via scanning electron microscopy (SEM) and water contact angle measurements. The performance of the fabricated membranes was evaluated using a bench scale cross-flow filtration unit. According to analysis of variance (ANOVA), all four independent parameters are statistically significant and the final model is reasonably accurate. Response surfaces and contours are plotted to represent the regression equations and their interpretation. Furthermore, the optimal experimental conditions for both water permeation flux and rejection were separately evaluated. The maximum permeation flux of 159.84 kg m⁻² h⁻¹ and rejection of 78.41% were achieved under the optimal fabrication parameters. Deviations between the predicted and actual responses of permeation flux and rejection were within 10% and 3%, respectively, which confirm the accuracy and validation of the model.