Response surface methodology (RSM) is widely applied to gathering knowledge on the interactions among parameters that require optimization during the treatment of wastewater. It can be used to optimize parameters during the process of treating wastewater, e.g., landfill leachate. The experimental design methods are useful to evaluate the parameters involved in a treatment with the minimum number of experiments. This will reduce the need for reagents and materials for experiments, which finally causes both time and expense to be increased. Anaerobic digestion of wastewater technologies escalated depending on the design configuration of the reactor. Several important parameters are taken into consideration in designing an anaerobic reactor such as operating conditions, seed sludge, wastewater composition and mixing. To construct a highly efficient degradation system, it is necessary to optimize such effective parameters. As a result, the advanced statistical design is used for process characterization, optimization and modelling. In this paper, the fundamentals of RSM and its application in the anaerobic treatment of wastewater was discussed in brief. The various works done in an anaerobic reactor using RSM for prediction and optimization are given.