The forward osmosis (FO) process is an emerging technology that has been considered as an alternative to desalination due to its low energy consumption and less severe reversible fouling. Artificial neural networks (ANNs) and response surface methodology (RSM) have become popular for the modeling and optimization of membrane processes. RSM requires the data on a specific experimental design whereas ANN does not. In this work, a combined ANN-RSM approach is presented to predict and optimize the membrane flux for the FO process. The ANN model, developed based on an experimental study, is used to predict the membrane flux for the experimental design in order to create the RSM model for optimization. A Box–Behnken design (BBD) is used to develop a response surface design where the ANN model evaluates the responses. The input variables were osmotic pressure difference, feed solution (FS) velocity, draw solution (DS) velocity, FS temperature, and DS temperature. The R2 obtained for the developed ANN and RSM model are 0.98036 and 0.9408, respectively. The weights of the ANN model and the response surface plots were used to optimize and study the influence of the operating conditions on the membrane flux.