This study investigated the application of adaptive neural fuzzy inference system (ANFIS) and Fuzzy c-means (FCM) algorithm for the simulation and prediction of 4-chlorophenol elimination in aqueous media by the persulfate/Nano zero valent iron process. The structure of developed model which resulted to the minimum value of mean square error was a Gaussian membership function with a total number 10 at input layer, a linear membership function at output layer and a hybrid optimum method, which is a combination of backpropagation algorithm and least squares estimation, for optimization of Gaussian membership function parameters. The prediction of developed model in elimination 4-chlorophenol was significantly close to the observed experimental results with R2 value of 0.9942. The results of sensitivity analysis indicated that all operating variables had a strong effect on the output of model (4-CP elimination). However, the most effective variable was pH followed by persulfate, NZVI dosage, reaction time and 4-CP concentration. The performance of developed model was also compared with a quadratic model generated in a study by Response Surface Methodology (RSM). The results indicated that the ANFIS-FCM model was superior to the quadratic model in terms of prediction accuracy and capturing the behavior of the process.